Production method of hexahydrofurofuranol derivative, intermediate therefor and production method thereof

ABSTRACT

The present invention provides a method for producing compound (XIV) useful as an intermediate for pharmaceutical agents efficiently and economically on an industrial scale without using ozone oxidation and highly toxic reagent, and an intermediate used for this method. Particularly, the present invention provides a method for producing a compound having an absolute configuration represented by the formula (XV) and an enantiomer thereof without using a technique such as optical resolution and the like, and an intermediate used for this method.
 
(1) Compound (XIII) as a starting material is led to compound (I), and after introducing a protecting group, subjected to reduction and cyclization to give compound (XIV). Particularly, compound (XIII) as a material is led to compound (I) via compound (XX) to produce compound (XIV). Using an optically active compound (XIII) as a starting material, a compound having an absolute configuration represented by the formula (XV) and the like are produced highly stereoselectively. (2) Compound (XXI) as a starting material is stereoselectively reduced to give compound (XXII), and by introduction of a protecting group, reduction and cyclization, compound (XXVI) is obtained, and by inverting hydroxyl group, compound (XV) is produced. 
                 
 
wherein each symbol is as defined in the specification.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a production method of ahexahydrofurofuranol derivative represented by the formula (XI),particularly the formula (XV), to be mentioned below, which is anintermediate for a pharmaceutical product, compounds represented by theformulas (A), (B) and (C) to be mentioned below, which are useful assynthetic intermediates therefor and production methods thereof.

BACKGROUND OF THE INVENTION

A compound represented by the formula (XIV):

particularly the formula (XV):

is a compound useful as an intermediate for an anti-AIDS drug(International Publication No. 01/25240 and International PublicationNo. 99/67254). As a method for synthesizing a compound represented bythe formula (XIV) or (XV), the methods described in InternationalPublication No. 01/25240, EP-A-539192, Tetrahedron Letters, 27, p. 3715(1986) and Tetrahedron Letters, 4, p. 505 (1995) are known. However,they use ozone oxidation and tributyltin hydride etc. having hightoxicity, and are not industrially preferable methods. Of theabove-mentioned references, International Publication No. 01/25240,EP-A-539192 and Tetrahedron Letters, 4, p. 505 (1995) comprise opticalresolution of the obtained racemate with an enzyme and the like to givean optically active compound, whose relative configuration isrepresented by the formula (XV), and are inefficient. Recently, a methodfor directly synthesizing an optically active compound, whose relativeconfiguration is represented by the formula (XV), has been reported inTetrahedron Letters, 42, p. 4653 (2001). This method, too, uses anorganic selenium compound having high toxicity, and is not entirely anindustrial method.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a method for producinga compound represented by the formula (XIV) (hereinafter to be alsoreferred to as compound (XIV)), which is useful as an intermediate foran anti-AIDS drug, efficiently and economically on an industrial scaleby resolving the problems of conventional production methods, such asozone oxidation and use of highly toxic reagents, an intermediate usedfor the method and a production method thereof, particularly, a methodfor producing compound (XIV) having an absolute configurationrepresented by the formula (XV) and an enantiomer thereof, without usinga technique such as optical resolution and the like, an intermediate forthe method and a production method thereof.

The present inventors have conducted intensive studies in an attempt tosolve the above-mentioned problems and, as a result, found a novelproduction method of compound (XIV), which comprises leading a compoundrepresented by the formula (XIII):

wherein P_(G) is a hydroxy-protecting group, and R₂ is a lower alkoxylgroup or a lower alkylthio group, used as a starting material, to acompound represented by the formula (I):

wherein P_(G) is as defined above, introducing a protecting group, whichis followed by reduction and cyclization to give compound (XIV), andnovel compounds represented by the formulas (A) and (B) to be mentionedbelow, which are intermediates for the method. Moreover, the presentinventors have found a novel production method of compound (XIV), whichcomprises leading a compound represented by the formula (XIII) used as astarting material to a compound represented by the formula (XIX):

wherein P_(G) and R₂ are as defined above, and R₃ is ahydroxy-protecting group or a hydrogen atom, hydrolyzing the compound togive a compound represented by the formula (XX):

wherein P_(G) and R₃ are as defined above, which is then processed togive a compound represented by the formula (I) or the formula (III):

wherein R₄ and R₅ are the same or different and each independently is ahydrogen atom, a lower alkyl group, a lower alkoxyl group or a phenylgroup, which is an intermediate for the aforementioned method, as wellas a novel compound represented by the formula (C) to be mentionedbelow, which is an intermediate for the method.

According to the method of the present invention, compound (XIV) can beproduced efficiently and economically on an industrial scale withoutusing highly toxic reagents or ozone oxidation which is difficult topractice on an industrial scale. Moreover, the present inventors havefound that a compound represented by the formula (XIII) can be led to acompound whose absolute configuration is represented by the formula(VII):

wherein P_(G) is as defined above, or an enantiomer thereof, highlystereoselectively at a superior optical purity, using an opticallyactive form of the formula (XIII), particularly an optically active formhaving a high optical purity, as a starting material according to theabove-mentioned method, without using a technique such as opticalresolution and the like, since an optically active form of the compoundrepresented by the formula (III) can be produced economically on anindustrial scale using a BINAP catalyst or a biological catalyst (U.S.Pat. No. 5,399,722, Heterocycles, 26, 2841 (1987)), and that a compoundwhose absolute configuration is represented by the formula (VII) or anenantiomer thereof can be led highly stereoselectively at a superioroptical purity to a compound whose absolute configuration is representedby the formula (XV) or an enantiomer thereof, which resulted in thecompletion of the present invention.

Particularly, they have found that, according to the method of thepresent invention that proceeds via carboxylic-acid represented by theaforementioned formula (XX), a compound whose absolute configuration isa compound represented by the formula (XVIII):

wherein P_(G) and R₃ are as defined above, or an enantiomer thereof canbe obtained highly stereoselectively at a superior optical purity byapplying purification when going through said carboxylic acid, therebyincreasing the diastereomer purity, and that a compound having anabsolute configuration represented by the formula (XVIII) or anenantiomer thereof can be led highly stereoselectively at a superioroptical purity to a compound whose absolute configuration is representedby the formula (XV) or an enantiomer thereof, which resulted in thecompletion of the present invention.

Since the present invention does not use ozone oxidation or a highlytoxic reagent, it is a useful production method of an optically activeform, as well as a superior production method of a racemate as comparedto conventional methods.

The present inventors have further conducted intensive studies to solvethe above-mentioned problems, and as a result, found a novel productionmethod of a compound having a relative configuration represented by theformula (XV) by stereoselectively reducing a compound represented by theformula (XXI):

wherein P_(G2) is a hydroxy-protecting group (hereinafter to be alsoreferred to as compound (XXI)) used as a starting material, to give acompound having a relative configuration represented by the formula(XXII):

wherein P_(G2) is as defined above, introducing a protecting group,reducing and cyclizing the compound to give a compound having a relativeconfiguration represented by the formula (XXVI):

and inverting a hydroxyl group to give a compound having a relativeconfiguration represented by the formula (XV), and novel compoundshaving relative configurations represented by the formulas (G) and (H)to be mentioned below, which is an intermediate therefor.

According to the method of the present invention, a compound having arelative configuration represented by the formula (XV), particularly, acompound having an absolute configuration represented by the formula(XV) and an enantiomer thereof can be produced efficiently andeconomically on an industrial scale without using a highly toxic reagentor ozone oxidation difficult to practice on an industrial scale, whichresulted in the completion of the present invention.

Accordingly, the present invention provides the following.

-   (1) A compound represented by the formula (A):    wherein R and R₁ are the same or different and each independently is    a hydroxy-protecting group or a hydrogen atom, or taken together to    represent a group of the formula:    wherein R₄ and R₅ are the same or different and each independently    is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a    phenyl group, provided that when R₁ is a hydrogen atom, R is a    hydroxy-protecting group, and a relative configuration of the    compound of the formula (A) is syn, then R should be a    hydroxy-protecting group other than benzyl group.-   (2) A compound represented by the formula (B):    wherein R and R₁ are the same or different and each independently is    a hydroxy-protecting group or a hydrogen atom, or taken together to    represent a group of the formula:    wherein R₄ and R₅ are the same or different and each independently    is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a    phenyl group.-   (3) The compound of the above-mentioned (1), which has a relative    configuration represented by the formula (D):    wherein R and R₁ are as defined in the above-mentioned (1).-   (4) The compound of the above-mentioned (2), which has a relative    configuration represented by the formula (E):    wherein R and R₁ are as defined in the above-mentioned (2).-   (5) The compound of the above-mentioned (1), which has an absolute    configuration represented by the formula (D), or an enantiomer    thereof.-   (6) The compound of the above-mentioned (2), which has an absolute    configuration represented by the formula (E), or an enantiomer    thereof.-   (7) The compound of the above-mentioned (1), (3) or (5), wherein R₁    is a hydrogen atom and R is a t-butyl group.-   (8) The compound of any of the above-mentioned (1) to (6), wherein R    and R₁ are taken together to represent a group of the formula:    wherein R₄ and R₅ are methyl groups.-   (9) The compound of any of the above-mentioned (1) to (6), wherein R    is a benzyl group or a t-butyl group and R₁ is a 1-ethoxyethyl group    or a 3, 4, 5, 6-tetrahydro-2H-pyran-2-yl group.-   (10) The compound of the above-mentioned (3) or (5), wherein R₁ is a    hydrogen atom and R is a benzyl group.-   (11) A compound represented by the formula (C):    wherein R, R₁ and R₃ are the same or different and each    independently is a hydroxy-protecting group or a hydrogen atom and    R₆ is a hydroxyl group, a lower alkoxyl group or a lower alkylthio    group, or a salt thereof.-   (12) The compound of the above-mentioned (11), which has an absolute    configuration represented by the formula (F):    wherein R, R₁, R₃ and R₆ are as defined in the above-mentioned (11),    or an enantiomer thereof.-   (13) The compound of the above-mentioned (11) or (12), wherein R is    a benzyl group, R₁ is a hydrogen atom, R₃ is a benzyl group or a    t-butyl group, and R₆ is a hydroxyl group or an ethoxy group.-   (14) A compound whose relative configuration is represented by the    formula (G):    wherein R₇ and R₈ are the same or different and each independently    is a hydroxy-protecting group or a hydrogen atom, or taken together    to represent a group represented by the formula:    wherein R₁₀ and R₁₁ are the same or different and each independently    is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a    phenyl group, provided that when R₈ is a hydrogen atom, and R₇ is a    hydroxy-protecting group, then R₇ should be a hydroxy-protecting    group other than a benzyl group.-   (15) A compound whose relative configuration is represented by the    formula (H):    wherein R₇ and R₈ are the same or different and each independently    is a hydroxy-protecting group or a hydrogen atom, or taken together    to represent a group represented by the formula:    wherein R₁₀ and R₁₁, are the same or different and each    independently is a hydrogen atom, a lower alkyl group, a lower    alkoxyl group or a phenyl group.-   (16) The compound of the above-mentioned (14), which has an absolute    configuration represented by the formula (G), or an enantiomer    thereof.-   (17) The compound of the above-mentioned (15), which has an absolute    configuration represented by the formula (H), or an enantiomer    thereof.-   (18) A production method of a compound represented by the formula    (I), which comprises hydroxyethylation of a compound represented by    the formula (XIII), followed by cyclization.-   (19) The production method of the above-mentioned (18), wherein the    compound represented by the formula (I) has a relative configuration    represented by the formula (VII).-   (20) The production method of the above-mentioned (18) or (19),    wherein the compound represented by the formula (XIII) is in an    optically active form.-   (21) The production method of the above-mentioned (18), wherein the    compound represented by the formula (XIII) is a compound represented    by the formula (XVI):    wherein each symbol is as defined in the above-mentioned (18), and    the compound represented by the formula (I) is a compound having an    absolute configuration represented by the formula (VII), or the    compound represented by the formula (XIII) is a compound represented    by the formula:    wherein each symbol is as defined in the above-mentioned (18), and    the compound represented by the formula (I) is an enantiomer of the    compound having an absolute configuration represented by the formula    (VII).-   (22) The production method of the above-mentioned (18), which    comprises hydroxyethylating a compound represented by the    formula (XIII) to give a compound represented by the formula (XIX),    hydrolyzing the obtained compound represented by the formula (XIX)    to give a compound represented by the formula (XX), and cyclizing    the obtained compound represented by the formula (XX) to give the    compound represented by the formula (I).-   (23) The production method of the above-mentioned (22), wherein the    compound represented by the formula (XIII) is a compound represented    by the formula (XVI), the compound represented by the formula (XIX)    is a compound having an absolute configuration represented by the    formula (XVII):    wherein each symbol is as defined in the above-mentioned (22), the    compound represented by the formula (XX) is a compound having an    absolute configuration represented by the formula (XVIII), and the    compound represented by the formula (I) is a compound having an    absolute configuration represented by the formula (VII), or the    compound represented by the formula (XIII) is an enantiomer of the    compound represented by the formula (XVI), the compound represented    by the formula (XIX) is an enantiomer of the compound having an    absolute configuration represented by the formula (XVII), the    compound represented by the formula (XX) is an enantiomer of the    compound having an absolute configuration represented by the formula    (XVIII), and the compound represented by the formula (I) is an    enantiomer of the compound having an absolute configuration    represented by the formula (VII).-   (24) A production method of a compound represented by the formula    (III), which uses a compound represented by the formula (I) as a    material.-   (25) The production method of the above-mentioned (24), comprising    deprotecting the compound represented by the formula (I) to give a    compound represented by the formula (II):    and converting the obtained compound represented by the formula (II)    to the compound represented by the formula (III).-   (26) A production method of a compound represented by the formula    (V):    wherein R₄ and R₅ are the same or different and each independently    is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a    phenyl group, which comprises reducing a compound represented by the    formula (III).-   (27) A production method of a compound represented by the formula    (XIV), which comprises subjecting a compound represented by the    formula (V) to deprotection and cyclization.-   (28) A production method of a compound represented by the formula    (IV):    wherein P_(G) and P_(G1) are the same or different and each    independently is a hydroxy-protecting group, which comprises    protecting a hydroxyl group of a compound represented by the formula    (I).-   (29) A production method of a compound represented by the formula    (VI):    wherein P_(G) and P_(G1) are the same or different and each    independently is a hydroxy-protecting group, which comprises    reducing a compound represented by the formula (IV).-   (30) A production method of a compound represented by the formula    (XIV), which comprises subjecting a compound represented by the    formula (VI) to deprotection and cyclization.-   (31) A production method of a compound represented by the formula    (XIV), which comprises either the following step (1A) or (1B);-   (1A) a step comprising obtaining a compound represented by the    formula (III) from a compound represented by the formula (I) as a    material,    reducing the obtained compound represented by the formula (III) to    give a compound represented by the formula (V), and subjecting the    obtained compound represented by the formula (V) to deprotection and    cyclization to give the above-mentioned compound represented by the    formula (XIV),-   (1B) a step comprising protecting a hydroxyl group of the compound    represented by the formula (I) to give a compound represented by the    formula (IV),    reducing the obtained compound represented by the formula (IV) to    give a compound represented by the formula (VI), and subjecting the    obtained compound represented by the formula (VI) to deprotection    and cyclization to give the above-mentioned compound represented by    the formula (XIV).-   (32) The production method of the above-mentioned (31), wherein, in    step (1A), the compound represented by the formula (I), which is a    material, is deprotected to give a compound represented by the    formula (II) and the obtained compound represented by the    formula (II) is converted to the compound represented by the formula    (III).-   (33) The production method of the above-mentioned (31) or (32),    wherein the compound represented by the formula (I) is a compound    having a relative configuration represented by the formula (VII),    and the compound represented by the formula (XIV) is a compound    having a relative configuration represented by the formula (XV).-   (34) The production method of the above-mentioned (31) or (32),    wherein the compound represented by the formula (I) is a compound    having an absolute configuration represented by the formula (VII),    and the compound represented by the formula (XIV) is a compound    having an absolute configuration represented by the formula (XV), or    the compound represented by the formula (I) is an enantiomer of the    compound having an absolute configuration represented by the formula    (VII), and the compound represented by the formula (XIV) is an    enantiomer of the compound having an absolute configuration    represented by the formula (XV).-   (35) A production method of a compound represented by the formula    (XIX), which uses a compound represented by the formula (XIII) as a    material.-   (36) A production method of a compound represented by the formula    (XX), which comprises hydrolysis of a compound represented by the    formula (XIX).-   (37) The production method of the above-mentioned (36), which    comprises addition of an organic amine after hydrolysis.-   (38) The production method of the above-mentioned (36), wherein the    compound represented by the formula (XIX) is produced using a    compound represented by the formula (XIII) as a material.-   (39) A production method of a compound represented by the formula    (III), which comprises acetalization or ketalization and    lactonization after deprotection of P_(G) and R₃ of a compound    represented by the formula (XX).-   (40) The production method of the above-mentioned (39), wherein the    compound represented by the formula (XX) is obtained using a    compound represented by the formula (XIII) as a starting material.-   (41) A production method of a compound represented by the formula    (XIV), which comprises obtaining a compound represented by the    formula (XIX) using a compound represented by the formula (XIII) as    a material, hydrolyzing the obtained compound represented by the    formula (XIX) to give a compound represented by the formula (XX),    deprotecting P_(G) and R₃ of the obtained compound represented by    the formula (XX), thereafter acetalizing or ketalizing and    lactonizing the compound to give a compound represented by the    formula (III), reducing the obtained compound represented by the    formula (III) to give a compound represented by the formula (V) and    subjecting the obtained compound represented by the formula (V) to    deprotection and cyclization.-   (42) The production method of the above-mentioned (41), wherein the    compound represented by the formula (XIII) is a compound represented    by the formula (XVI), the compound represented by the formula (XIX)    is a compound having an absolute configuration represented by the    formula (XVII), the compound represented by the formula (XX) is a    compound having an absolute configuration represented by the formula    (XVIII), the compound represented by the formula (III) is a compound    having an absolute configuration represented by the formula (IX):    wherein R₄ and R₅ are the same or different and each independently    is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a    phenyl group, the compound represented by the formula (V) is a    compound having an absolute configuration represented by the formula    (XI):    wherein R₄ and R₅ are the same or different and each independently    is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a    phenyl group, and the compound represented by the formula (XIV) is a    compound having an absolute configuration represented by the formula    (XV), or the compound represented by the formula (XIII) is an    enantiomer of the compound represented by the formula (XVI), the    compound represented by the formula (XIX) is an enantiomer of the    compound having an absolute configuration represented by the formula    (XVII), the compound represented by the formula (XX) is an    enantiomer of the compound having an absolute configuration    represented by the formula (XVIII), the compound represented by the    formula (III) is an enantiomer of the compound having an absolute    configuration represented by the formula (IX), the compound    represented by the formula (V) is an enantiomer of the compound    having an absolute configuration represented by the formula (XI),    and the compound represented by the formula (XIV) is an enantiomer    of the compound having an absolute configuration represented by the    formula (XV).-   (43) A production method of a compound having a relative    configuration represented by the formula (XXII), which comprises    stereoselective reduction of a compound represented by the formula    (XXI).-   (44) The production method of the above-mentioned (43), wherein the    compound having a relative configuration represented by the    formula (XXII) is a compound having an absolute configuration    represented by the formula (XXII) or an enantiomer thereof.-   (45) A production method of a compound having a relative    configuration represented by the formula (XXIV):    wherein R₁₀ and R₁₁ are the same or different and each independently    is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a    phenyl group, which comprises the following step (2A) or (2B):-   (2A) a step for simultaneously deprotecting and introducing a    protecting group using a compound having a relative configuration    represented by the formula (XXII) as a material to produce the    above-mentioned compound having a relative configuration represented    by the formula (XXIV)-   (2B) a step for deprotecting the compound having a relative    configuration represented by the formula (XXII) to give a compound    having a relative configuration represented by the formula (XXIII):    introducing a protecting group into the obtained compound having a    relative configuration represented by the formula (XXIII), to    produce the above-mentioned compound having a relative configuration    represented by the formula (XXIV).-   (46) A production method of a compound having a relative    configuration represented by the formula (XXV):    wherein R₁₀ and R₁₁ are the same or different and each independently    is a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a    phenyl group, which comprises reducing a compound having a relative    configuration represented by the formula (XXIV).-   (47) A production method of a compound having a relative    configuration represented by the formula (XXVI), which comprises    subjecting a compound having a relative configuration represented by    the formula (XXV) to deprotection and cyclization.-   (48) A production method of a compound having a relative    configuration represented by the formula (XXVI), which comprises    stereoselectively reducing a compound represented by the    formula (XXI) to give a compound having a relative configuration    represented by the formula (XXII), obtaining a compound having a    relative configuration represented by the formula (XXIV) using the    obtained compound having a relative configuration represented by the    formula (XXII) as a material, reducing the obtained compound having    a relative configuration represented by the formula (XXIV) to give a    compound having a relative configuration represented by the formula    (XXV), and subjecting the obtained compound having a relative    configuration represented by the formula (XXV) to deprotection and    cyclization.-   (49) The production method of the above-mentioned (48), wherein the    compound having a relative configuration represented by the    formula (XXII) is a compound having an absolute configuration    represented by the formula (XXII), the compound having a relative    configuration represented by the formula (XXIV) is a compound having    an absolute configuration represented by the formula (XXIV), the    compound having a relative configuration represented by the    formula (XXV) is a compound having an absolute configuration    represented by the formula (XXV), and the compound having a relative    configuration represented by the formula (XXVI) is a compound having    an absolute configuration represented by the formula (XXVI), or the    compound having a relative configuration represented by the    formula (XXII) is an enantiomer of the compound having an absolute    configuration represented by the formula (XXII), the compound having    a relative configuration represented by the formula (XXIV) is an    enantiomer of the compound having an absolute configuration    represented by the formula (XXIV), the compound having a relative    configuration represented by the formula (XXV) is an enantiomer of    the compound having an absolute configuration represented by the    formula (XXV), and the compound having a relative configuration    represented by the formula (XXVI) is an enantiomer of the compound    having an absolute configuration represented by the formula (XXVI).-   (50) The production method of the above-mentioned (43), (44), (48)    or (49), wherein the stereoselective reduction is an asymmetric    hydrogenation reaction using a transition metal catalyst having an    asymmetric ligand.-   (51) The production method of the above-mentioned (50), wherein the    transition metal catalyst has an asymmetric ligand which is an    optically active phosphine derivative selected from the group    consisting of the compounds represented by the following formulas:    wherein Ra, Rb, Rd, Re, Rh, Ri, Rj, Rk, Rl, Rm, Rn and Ro are the    same or different and each independently is an optionally    substituted phenyl or an optionally substituted cyclohexyl, Rc, Rf    and Rg are the same or different and each independently is a    hydrogen atom, a halogen atom, alkyl, alkoxy or an optionally    substituted phenyl and l, m, n and o are each independently an    integer of 1-6, (hereinafter to be also respectively referred to as    compounds (L1)-(L6)) and enantiomers thereof, and a transition    metal, which is ruthenium.-   (52) The production method of the above-mentioned (51), wherein the    asymmetric ligand is an optically active phosphine derivative    selected from the group consisting of the compounds of the formulas    (L1), (L2), (L3), (L4), (L5) and (L6), and the compound having a    relative configuration represented by the formula (XXII) is a    compound having an absolute configuration represented by the formula    (XXII), or an asymmetric ligand is an optically active phosphine    derivative selected from the group consisting of enantiomers of the    compounds of the formulas (L1), (L2), (L3), (L4), (L5) and (L6), and    the compound having a relative configuration represented by the    formula (XXII) is an enantiomer of the compound having an absolute    configuration represented by the formula (XXII).-   (53) A production method of a compound having a relative    configuration represented by the formula (XV), which comprises    inverting a hydroxyl group of a compound having a relative    configuration represented by the formula (XXVI).-   (54) The production method of the above-mentioned (53), which    comprises the following step (2C) or (2D):-   (2C) a step comprising oxidation of the above-mentioned compound    having a relative configuration represented by the formula (XXVI) to    give a compound having a relative configuration represented by the    formula (XXVII):    reducing the obtained compound having a relative configuration    represented by the formula (XXVII) to give the above-mentioned    compound having a relative configuration represented by the formula    (XV),-   (2D) a step comprising inversion esterification of the    above-mentioned compound having a relative configuration represented    by the formula (XXVI) as a material to give a compound having a    relative configuration represented by the formula (XXVIII):    wherein R₉ is alkanoyl group wherein hydrogen atom is optionally    substituted by fluorine atom or chlorine atom, or a benzoyl group    wherein hydrogen atom of phenyl group is optionally substituted by    nitro group, halogen, alkyl group, alkoxyl group or phenyl group,    and hydrolyzing the obtained compound having a relative    configuration represented by the formula (XXVIII) to give the    above-mentioned compound having a relative configuration represented    by the formula (XV).-   (55) The production method of the above-mentioned (54), wherein the    inversion esterification in step (2D) is carried out in the presence    of triphenylphosphine or trialkylphosphine and azodicarboxylic acid    ester or azodicarboxylic amide.-   (56) The production method of any of the above-mentioned (53)-(55),    wherein the compound having a relative configuration represented by    the formula (XXVI) is a compound having an absolute configuration    represented by the formula (XXVI), and the compound having a    relative configuration represented by the formula (XV) is a compound    having an absolute configuration represented by the formula (XV), or    the compound having a relative configuration represented by the    formula (XXVI) is an enantiomer of the compound having an absolute    configuration represented by the formula (XXVI), and the compound    having a relative configuration represented by the formula (XV) is    an enantiomer of the compound having an absolute configuration    represented by the formula (XV).

DETAILED DESCRIPTION OF THE INVENTION

In the following, the compounds represented by the formulas (A), (B),(C), (I)-(VI), (XIII), (XIX) and (XX) are sometimes to be referred to ascompounds (A), (B), (C), (I)-(VI), (XIII), (XIX) and (XX), respectively.

The compounds (A), (B), (C), (I)-(VI), (XIX) and (XX) of the presentinvention are not particularly limited as regards the configurationthereof and encompass any embodiments including each isomer, a mixturethereof at an optional proportion and the like.

The compounds (XIII) and (XI) are not particularly limited as regardsconfiguration unless particularly indicated, and encompass anyembodiments including each isomer, mixtures thereof at an optionalproportion and the like.

The optically active form in the context of the present specification isused to mean non-racemic. For example, the optically active formincludes a mixture of 70% S-form and 30% R-form and a mixture of 70%(S,S)-form and 30% (R,R)-form.

As compound (A), for example, compounds (I), (II), (III), (IV) and thelike can be mentioned. As compound (B), for example, compounds (V), (VI)and the like can be mentioned. As compound (C), for example, compounds(XIX), (XX) and the like can be mentioned.

As a compound whose relative configuration is represented by the formula(D), for example, compounds whose relative configurations arerepresented by the formulas:

wherein each symbol is as defined above, and the like can be mentioned.

As a compound whose relative configuration is represented by the formula(E), for example, compounds whose relative configurations arerepresented by the formulas:

wherein each symbol is as defined above, and the like can be mentioned.

As a preferable compound whose absolute configuration is represented bythe formula (D), for example, a compound whose absolute configuration isrepresented by the formula:

and the like can be mentioned.

As a compound whose absolute configuration is represented by the formula(F), for example, compounds whose absolute configurations arerepresented by the formulas (XVII) and (XVIII) and the like can bementioned, and as a preferable compound whose absolute configuration isrepresented by the formula (F), compounds whose absolute configurationsare represented by the formulas:

wherein -Bn is a benzyl group and-t-Bu is a t-butyl group, and the likecan be mentioned.

As the salts of the compounds represented by the formulas (C) and (F),for example, salts with a base such as organic amine (e.g.,dibenzylamine, benzylamine, dicyclohexylamine, cyclohexylamine,(S)-phenethylamine etc.), an alkali metal (e.g., potassium, sodium,lithium etc.), an alkaline earth metal (e.g., magnesium, calcium, bariumetc.), and a basic amino acid (e.g., L-phenylalanine methyl ester,glycine methyl ester etc.) can be mentioned. Preferred are a salt withorganic amine and a salt with an alkali metal, and particularlypreferred are dibenzylamine salt and potassium salt. The organic amineand basic amino acid may be racemates or optical isomers.

The compound whose relative configuration is represented by the formula(D) refers to a compound whose absolute configuration is represented bythe formula (D) or an enantiomer thereof, or a mixture of a compoundwhose absolute configuration is represented by the formula (D) and anenantiomer thereof at an optional proportion (including racemates).

The relative configuration of the compound whose relative configurationis represented by the formula (E), the compound having a relativeconfiguration represented by the formula (VII), the compound having arelative configuration represented by the formula (XV) and the likemeans the same as in the compound whose relative configuration isrepresented by the formula (D).

In the formulas (A), (B), (C), (D), (E), (F), (I), (IV), (VI), (VII),(X), (XII), (XIII) and (XVI)-(XX), the hydroxy-protecting group for R,R₁, R₃, P_(G) and P_(G1) is exemplified by benzyl group, t-butyl group,1-ethoxyethyl group, 3,4,5,6-tetrahydro-2H-pyran-2-yl group,triphenylmethyl group, 1-methoxy-1-methylethyl group, methoxymethylgroup, ethoxymethyl group, triethylsilyl group, tri-n-butylsilyl group,t-butyldimethylsilyl group and the like, wherein R and P_(G) arepreferably benzyl group, t-butyl group and triphenylmethyl group, and R₁and P_(G1) are preferably 1-ethoxyethyl group and3,4,5,6-tetrahydro-2H-pyran-2-yl group. R₃ is preferably benzyl group ort-butyl group.

However, when, in the formula (A), R₁ is a hydrogen atom, R is ahydroxy-protecting group, and the relative configuration of compound (A)is syn, i.e., the relative configuration of compound (A) is representedby

R is a hydroxy-protecting group other than benzyl group.

In the formulas (A), (B), (D), (E), (III), (V), (IX) and (XI), the loweralkyl group for R₄ and R₅ is, for example, a straight chain or branchedchain alkyl group having 1 to 6, preferably 1 to 3, carbon atoms, whichis specifically, for example, methyl group, ethyl group, n-propyl group,isopropyl group and the like, wherein R₄ and R₅ are each preferably amethyl group.

In the formulas (A), (B), (D), (E), (III), (V), (IX) and (XI), the loweralkoxyl group for R₄ and R₅ is, for example, a straight chain orbranched chain alkoxyl group having 1 to 6, preferably 1 to 3, carbonatoms, which is specifically, for example, methoxy group, ethoxy group,n-propoxy group, isopropoxy group and the like.

In the formulas (C), (F), (XIII), (XVI), (XVII) and (XIX), the loweralkoxyl group for R₆ and R₂ is, for example, a straight chain orbranched chain alkoxy group having 1 to 6, preferably 1 to 4, carbonatoms, which is specifically, for example, methoxy group, ethoxy group,n-propoxy group, isopropoxy group, n-butoxy group, t-butoxy group andthe like, with preference given to methoxy group.

In the formulas (C), (F), (XIII), (XVI), (XVII) and (XIX), the loweralkylthio group for R₆ and R₂ is, for example, a straight chain orbranched chain alkylthio group having 1 to 6, preferably 1 to 4, carbonatoms, which is specifically, for example, methylthio group, ethylthiogroup, n-propylthio group, isopropylthio group, n-butylthio group,t-butylthio group and the like.

The compound having a relative configuration represented by the formula(XXII) refers to a compound whose absolute configuration is representedby the formula (XXII) or an enantiomer thereof, or a mixture of acompound whose absolute configuration is represented by the formula(XXII) and an enantiomer thereof at an optional proportion (includingracemates). The compounds having relative configurations represented bythe formulas (G), (H), (XXIII)-(XXVIII) and (XV) mean the same as in thecompound having relative configuration represented by the aforementionedformula (XXII). In the following, the compounds having relativeconfigurations represented by the formulas (G), (H) and (XXII)-(XXVIII)are referred to as compounds (G), (H) and (XXII)-(XXVIII), respectively.In the following, the compound having a relative configurationrepresented by the formula (XV) is also referred to as compound (XV).

As the compound (G), for example, compounds (XXII)-(XXIV) and the likecan be mentioned. As the compound (H), for example, compound (XXV) andthe like can be mentioned.

In the formulas (G) and (H), the hydroxy-protecting group for R₇ and R₈is, for example, benzyl group, tert-butyl group, 1-ethoxyethyl group,3,4,5,6-tetrahydro-2H-pyran-2-yl group, triphenylmethyl group,1-methoxy-1-methylethyl group, methoxymethyl group, ethoxymethyl group,triethylsilyl group, tri-n-butylsilyl group, tert-butyldimethylsilylgroup and the like. As R₇, benzyl group, tert-butyl group andtriphenylmethyl group are preferable. As R₈, 1-ethoxyethyl group and3,4,5,6-tetrahydro-2H-pyran-2-yl group are preferable. As thehydroxy-protecting group for P_(G2) in the formulas (XXI) and (XXII),the protecting groups mentioned for R₇ of the above-mentioned formulas(G) and (H) can be used.

However, for the compound (G) of the present invention, when, in theformula (G), R₈ is a hydrogen atom and R₇ is a hydroxy-protecting group,R₇ is a hydroxy-protecting group other than benzyl group.

In the formulas (G), (H), (XXIV) and (XXV), the lower alkyl group forR₁₀ and R₁₁ is, for example, a straight chain or branched chain alkylgroup having 1 to 6, preferably 1 to 3, carbon atoms, which isspecifically, for example, methyl group, ethyl group, n-propyl group,isopropyl group and the like, wherein R₁₀ and R₁₁ are each preferably amethyl group.

In the formulas (G), (H), (XXIV) and (XXV), the lower alkoxyl group forR₁₀ and R₁₁ is, for example, a straight chain or branched chain alkoxylgroup having 1 to 6, preferably 1 to 3, carbon atoms, which isspecifically, for example, a methoxy group, an ethoxy group, ann-propoxy group, an isopropoxy group and the like.

In the formula (XXVIII), the alkanoyl group of alkanoyl group for R₉wherein hydrogen atom is optionally substituted by fluorine atom orchlorine atom is, for example, a straight chain or branched chainalkanoyl group having 1 to 7, preferably 1 to 5, carbon atoms. As thealkanoyl group wherein hydrogen atom is optionally substituted byfluorine atom or chlorine atom, for example, formyl, acetyl,chloroacetyl, trifluoroacetyl, propanoyl, butanoyl, isobutanoyl,pivaloyl and the like, preferably, acetyl, trifluoroacetyl, pivaloyl andthe like, can be mentioned. The number of the substituents is notparticularly limited, but 1-3 is preferable, which substituents may bethe same or different.

In the formula (XXVIII), the number of the substituents of the benzoylgroup for R₉ wherein hydrogen atom of phenyl group is optionallysubstituted by nitro group, halogen, alkyl group, alkoxyl group orphenyl group is not particularly limited, but 1-3 is preferable, whichsubstituents may be the same or different. As the halogen for thesubstituent, fluorine atom, chlorine atom, bromine atom and iodine atomcan be mentioned, with preference given to fluorine atom, chlorine atomand the like. As the alkyl group for the substituent, for example, astraight chain or branched chain alkyl group having 1 to 6, preferably 1to 4, carbon atoms can be mentioned, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, isohexyl and the like, with preference given tomethyl, ethyl, tert-butyl and the like. As the alkoxyl group for thesubstituent, for example, a straight chain or branched chain alkoxylgroup having 1 to 8, preferably 1 to 4, carbon atoms can be mentioned,such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy and the like, with preference given to methoxy,ethoxy, tert-butoxy and the like.

The production methods of compound (XIV) of the present invention,particularly a compound represented by the formula (XV), are explainedin detail in the following. The production methods of compound (XIV) areshown in the following Scheme 1. Particularly, the production methods ofa compound, whose relative configuration or absolute configuration isrepresented by the formula (XV), are shown in Scheme 2.

The present invention is characterized by a method comprisinghydroxyethylation of compound (XIII), followed by cyclization to givecompound (I); a method for producing compound (III) using compound (I)as a material; a method for producing compound (V) by reducing compound(III); and a method comprising subjecting compound (V) to deprotectionand cyclization to give compound (XIV). The present invention is alsocharacterized by a method comprising protecting hydroxyl group ofcompound (I) to give compound (IV); a method comprising reducingcompound (IV) to give compound (VI); and a method comprising subjectingcompound (VI) to deprotection and cyclization to give compound (XIV).The above-mentioned methods of the present invention can be eachperformed independently, but two or more of the methods are preferablyperformed in combination.

wherein each symbol is as defined above.

wherein each symbol is as defined above.Production of Compound (I) from Compound (XIII)

The compound (XIII), which is a material, can be obtained by a knownmethod (e.g., method described in Heterocycles 26, 2841 (1987), U.S.Pat. No. 5,399,722 etc. and the like).

As regards compound (XIII), which is an optically active form, an R-formof compound (XIII) (to be also referred to as a compound of the formula(XVI) in the present specification) can be obtained according to amethod described in, for example, Heterocycles 26, 2841 (1987) and thelike, and an S-form (to be also referred to as an enantiomer of acompound of the formula (XVI) in the present specification) can beobtained according to a method described in, for example, U.S. Pat. No.5,399,722 and the like.

The compound (I) can be obtained by hydroxyethylation of compound(XIII), followed by cyclization. For example, compound (XIII) is reactedwith 2-(1-ethoxyethoxy)ethyl halide,2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl halide, 2-vinyloxyethylhalide, 2-(t-butoxy)ethyl halide, 2-trimethylsilyloxyethyl halide,2-triethylsilyloxyethyl halide, 2-t-butyldimethylsilyloxyethyl halide,ethylene oxide and the like, under addition of a base (e.g., lithiumdiisopropylamide, lithium hexamethyldisilazide, sodium hydride,potassium hydride and the like, preferably lithium diisopropylamide),and then cyclized.

The amount of the base to be used is generally 1.8-2.8 mol, preferably2-2.4 mol, per 1 mol of compound (XIII).

As 2-(1-ethoxyethoxy)ethyl halide, for example, 2-(1-ethoxyethoxy)ethyliodide, 2-(1-ethoxyethoxy)ethyl bromide and the like can be mentioned;as 2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl halide, for example,2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl iodide,2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl bromide and the like can bementioned; as 2-vinyloxyethyl halide, for example, 2-vinyloxyethyliodide, 2-vinyloxyethyl bromide and the like can be mentioned; as2-(t-butoxy)ethyl halide, for example, 2-(t-butoxy)ethyl iodide,2-(t-butoxy)ethyl bromide and the like can be mentioned; as2-trimethylsilyloxyethyl halide, for example, 2-trimethylsilyloxyethyliodide, 2-trimethylsilyloxyethyl bromide and the like can be mentioned;as 2-triethylsilyloxyethyl halide, for example, 2-triethylsilyloxyethyliodide, 2-triethylsilyloxyethyl bromide and the like can be mentioned;as 2-t-butyldimethylsilyloxyethyl halide, for example,2-t-butyldimethylsilyloxyethyl iodide, 2-t-butyldimethylsilyloxyethylbromide and the like can be mentioned. Of the above-mentioned reagentsfor the hydroxyethylation, 2-(1-ethoxyethoxy)ethyl iodide,2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl iodide, 2-vinyloxyethyliodide, 2-(t-butoxy)ethyl iodide, 2-trimethylsilyloxyethyl iodide,2-triethylsilyloxyethyl iodide, 2-t-butyldimethylsilyloxyethyl iodideand ethylene oxide are preferable.

The amount of the above-mentioned reagent to be used forhydroxyethylation, such as 2-(1-ethoxyethoxy)ethyl halide and the like,is generally 0.8-2 mol, preferably 1-1.5 mol, per 1 mol of compound(XIII).

This reaction is carried out in a reaction solvent such astetrahydrofuran (THF), methyl t-butyl ether (MTBE), ethylene glycoldimethyl ether, diethylene glycol dimethyl ether, 1,3-dioxolane,1,4-dioxane, methyl cyclopentyl ether and the like, preferably THF orMTBE. The amount of the reaction solvent to be used is 1-50 L,preferably 3-20 L, per 1 kg of compound (XIII).

The reaction temperature is generally −30° C. to 60° C., preferably 0 to30° C., and the reaction time is generally 1 hr-48 hr, preferably 3hr-24 hr.

The above-mentioned reagent for the hydroxyethylation can be produced bya known method. For example, 2-(1-ethoxyethoxy)ethyl iodide can beproduced by mixing 2-iodoethanol with ethyl vinyl ether in the presenceof p-toluenesulfonic acid; 2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyliodide can be produced by mixing 3,4-dihydro-2H-pyran with 2-iodoethanolin the presence of p-toluenesulfonic acid; 2-vinyloxyethyl iodide can beproduced by reacting 2-vinyloxyethanol with p-toluenesulfonyl chloridein the presence of triethylamine, and then mixing with sodium iodide inthe presence of sodium hydrogen carbonate; 2-(t-butoxy)ethyl iodide canbe produced by mixing isobutylene with 2-iodoethanol in the presence oftrifluoromethanesulfonic acid; 2-trimethylsilyloxyethyl iodide can beproduced by mixing trimethylsilyl chloride with 2-iodoethanol in thepresence of imidazole; 2-triethylsilyloxyethyl iodide can be produced bymixing triethylsilyl chloride with 2-iodoethanol in the presence ofimidazole; and 2-t-butyl dimethylsilyloxyethyl iodide can be produced bymixing t-butyldimethylsilyl chloride with 2-iodoethanol in the presenceof imidazole.

The compound (I) can be isolated by a conventional method. For example,the compound can be isolated by pouring a reaction mixture into aqueoushydrochloric acid, partitioning the mixture, washing the obtainedorganic layer with aqueous alkali solution and evaporating the solvent.For complete cyclization, the isolation product may be reacted in asolvent in the presence of an acid catalyst such as p-toluenesulfonicacid and the like, and then worked up again by a conventional method.The obtained isolate can be further purified by a conventional methodbut may be used in the next reaction without purification.

The compound (I) obtained by the above-mentioned method is mostlyobtained as a compound having a relative configuration represented bythe formula (VII). By recrystallization thereof from, for example,diisopropyl ether, a purer compound having a relative configurationrepresented by the formula (VII) can be obtained.

Using compound (XIII), which is an optically active form, as a materialfor the above-mentioned method, a compound having an absoluteconfiguration represented by the formula (VII) or an enantiomer thereofcan be obtained. While the optically active form includes an S-form ofcompound (XIII), an R-form of compound (XIII), and a mixture of S-formand R-form except racemate, of these, when an S-form of compound (XIII),i.e., a compound represented by the formula (XVI):

wherein each symbol is as defined above, is used as a material, acompound having an absolute configuration represented by the formula(VII) can be obtained, and when an R-form of compound (XIII), i.e., acompound represented by the formula:

wherein each symbol is as defined above, is used as a material, anenantiomer of a compound having an absolute configuration represented bythe formula (VII) can be obtained. When a mixture of S-form and R-format an optional proportion except racemate is used as a material, amixture of a compound having an absolute configuration represented bythe formula (VII) and an enantiomer thereof can be obtained. Bysubjecting the reaction product obtained by the above-mentioned methodto recrystallization using a suitable solvent such as diisopropyl ether,MTBE and the like, the proportion of either the compound having anabsolute configuration represented by the formula (VII) or theenantiomer thereof can be increased.Production of Compound (XIV) from Compound (I)

The compound (XIV) can be obtained by introducing a protecting groupinto compound (I), followed by reduction and cyclization. That is, thecompound is obtained by a step of, for example, the following (1A) or(1B).

Step (1A) includes obtaining compound (III) using compound (I) as amaterial, reducing the obtained compound (III) to give compound (V), andsubjecting the obtained compound (V) to deprotection and cyclization togive compound (XIV). In step (1B), hydroxyl group of compound (I) isprotected to give compound (IV), the obtained compound (IV) is reducedto give compound (VI) and the obtained compound (VI) is subjected todeprotection and cyclization to give compound (XIV).

Step (1A)

Production of Compound (III) from Compound (I)

The compound (III) can be produced by, for example, the following twomethods using compound (I) as a material. One of them is a methodcomprising deprotecting compound (I) to give compound (II), introducinga diol-protecting group into the obtained compound (II) to give compound(III) (hereinafter to be referred as Method (1)), and the other is amethod comprising directly protecting diol from compound (I) to givecompound (III) (hereinafter to be referred to as Method (2)). Eachmethod is explained in the following.

Method (1) (Method for Production of Compound (III) from Compound (I)via Compound (II))

The compound (II) can be obtained by deprotection of compound (I). Thedeprotecting reagent can be appropriately selected depending on the kindof the protecting group of compound (I). When the protecting group is at-butyl group, for example, compound (I) is reacted using an acid (e.g.,trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonicacid, strong acidic ion-exchange resin and the like, preferablytrifluoroacetic acid) generally at −20° C. to 80° C., preferably 0° C.to 30° C., generally for 1 min-5 hr, preferably 15 min-3 hr, fordeprotection. The acid is used in an amount of generally 0.01-10 L,preferably 0.1-5 L, per 1 kg of compound (I). After the completion ofthe reaction, compound (II) can be isolated by evaporating the acid or,after neutralization by a conventional method, by extracting with anorganic solvent and evaporating the solvent.

When the protecting group is a benzyl group, for example, compound (I)is deprotected by a reaction in a solvent (e.g., ethyl acetate, ethanol,methanol, acetic acid, THF and the like, preferably ethyl acetate,acetic acid), using a catalyst (e.g., Pd/C, Pd(OH)₂ and the like,preferably Pd/C) generally at −20° C. to 100C., preferably 0° C. to 50°C., under a hydrogen atmosphere generally for 0.5-12 hr, preferably 1-6hr.

The amount of the solvent to be used is generally 1-50 L, preferably3-25 L, per 1 kg of compound (I). The amount of the reduction catalystto be used is generally 0.00001-0.5 kg, preferably 0.0001-0.2 kg, per 1kg of compound (I).

The compound (II) can be isolated by evaporating the solvent afterfiltering off the catalyst.

The protecting reagent to be used for converting the obtained compound(II) to compound (III) varies depending on the kind of R₄ and R₅, whichare the constituent elements of the protecting group, and when, forexample, both R₄ and R₅ are methyl groups, 2,2-dimethoxypropane oracetone can be used. In this case, the obtained compound (II) can beprotected by reacting the compound with 2,2-dimethoxypropane or acetoneusing an acid (e.g., p-toluenesulfonic acid, pyridiniump-toluenesulfonate, methanesulfonic acid, sulfuric acid, acidicion-exchange resin, boron trifluoride and the like, preferablyp-toluenesulfonic acid, pyridinium p-toluenesulfonate) generally at −20°C. to 100° C., preferably 0° C. to 50° C., for generally 0.5-12 hr,preferably 1-6 hr. When both R₄ and R₅ are lower alkyl groups, thereaction can be carried out according to the above-mentioned method.

The amount of the protecting reagent, such as 2,2-dimethoxypropane andthe like, to be used is generally 0.5-50 L, preferably 3-20 L, per 1 kgof compound (II). The amount of the acid to be used is generally0.0001-0.5 kg, preferably 0.0005-0.2 kg, per 1 kg of compound (II).

The compound (III) can be isolated by a conventional method. Forexample, when an acid is used as mentioned above, the compound can beisolated by neutralizing the reaction mixture with an aqueous alkalisolution, partitioning the mixture, washing the obtained organic layerwith aqueous alkali solution and evaporating the solvent. The isolatecan be purified by a conventional method but may be used in the nextreaction without purification.

Method (2) (Method for Directly Producing Compound (III) from Compound(I))

The deprotection of compound (I) and protection of diol group aresimultaneously conducted to directly obtain compound (III). While thismethod is performed by simultaneously adding a deprotecting reagent anda protecting reagent, which are used in the above-mentioned method (1),the reagents are appropriately determined according to the kinds of thegroup to be deprotected and the protecting group of diol. In thefollowing, an example is taken for explanation, where the group to bedeprotected in compound (I) is a benzyl group and the diol-protectinggroup is a dimethylmethylene group, but the present invention is notlimited by this method.

For example, when the protecting group of compound (I) is a benzyl groupand the diol-protecting group is a dimethylmethylene group, compound (I)and 2,2-dimethoxypropane and/or acetone, which is a protecting reagent,which is a protecting reagent, are reacted in a solvent (e.g., THF,ethyl acetate and the like, preferably THF) or without solvent, using acatalyst (e.g., Pd/C, Pd(OH)₂ and the like, preferably Pd/C) and anacidic ion-exchange resin (e.g., Amberlyst 15E (manufactured by Rohm &Haas), Nafion SAC13 (manufactured by Dupont) etc.) or an acid (e.g.,phosphoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonicacid, boron trifluoride, phosphorus oxychloride etc.) generally at −20°C. to 100° C., preferably 0° C. to 50° C., under a hydrogen atmospheregenerally for 0.5-12 hr, preferably 1-6 hr to give compound (III).

The amount of the protecting reagent, such as 2,2-dimethoxypropane andthe like, to be used is generally 0.5-100 L, preferably 1-50 L, per 1 kgof compound (I). The amount of the reduction catalyst to be used isgenerally 0.0001-0.5 kg per 1 kg of compound (I). The amount of theacidic ion-exchange resin to be used is generally 0.001-0.5 kg,preferably 0.005-0.1 kg, per 1 kg of compound (I). When other acid isused, the amount of the acid to be used is generally 0.00001-0.1 kg,preferably 0.0001-0.01 kg, per 1 kg of compound (I). When a solvent isused, the amount of the solvent to be used is generally 0.5-50 L,preferably 1-25 L, per 1 kg of compound (I).

The compound (III) can be isolated by evaporating the solvent afterfiltering off the catalyst. The isolate can be purified by aconventional method but may be used in the next reaction withoutpurification.

When R₄ is a hydrogen atom and R₅ is a lower alkyl group or a phenylgroup, which are the constituent elements of the protecting group, thereaction can be carried out in the same manner as in the above-mentionedMethods (1) and (2), using alkanal or benzaldehyde, and/or acetal ofalkanal or benzaldehyde (e.g., dimethyl acetal etc.) instead of2,2-dimethoxypropane or acetone for the above-mentioned Methods (1) and(2).

When R₄ is a lower alkyl group or a phenyl group and R₅ is a lower alkylgroup or a phenyl group, the reaction can be generally carried out inthe same manner as in the above-mentioned Methods (1) and (2), usingR₄COR₅ and/or acetal thereof (e.g., dimethyl acetal etc.) instead of2,2-dimethoxypropane or acetone for the above-mentioned Methods (1) and(2).

When R₄ is a lower alkyl group or a phenyl group and R₅ is a loweralkoxyl group, the reaction can be carried out in the same manner as inthe above-mentioned Methods (1) and (2), using trialkyl orthoalkanoate(e.g., MeC(OEt)₃ etc.) or trialkyl orthobenzoate instead of2,2-dimethoxypropane or acetone for the above-mentioned Methods (1) and(2).

When R₄ is a hydrogen atom and R₅ is a lower alkoxyl group, the reactioncan be carried out in the same manner as in the above-mentioned Methods(1) and (2), using trialkyl orthoformate instead of 2,2-dimethoxypropaneor acetone for the above-mentioned Methods (1) and (2).

When R₄ and R₅ are lower alkoxyl groups, the reaction can be carried outin the same manner as in the above-mentioned Methods (1) and (2), usingtetraalkyl orthocarbonate instead of 2,2-dimethoxypropane or acetone forthe above-mentioned Methods (1) and (2).

The compounds having relative configurations represented by the formulas(VIII) and (IX) can be produced according to the above-mentioned Methods(1) and (2), using a compound having a relative configurationrepresented by the formula (VII) as a material.

The compounds having absolute configurations represented by the formulas(VIII) and (IX) can be produced according to the above-mentioned Methods(1) and (2), using a compound having an absolute configurationrepresented by the formula (VII) as a material. The enantiomers of thecompounds having absolute configurations represented by the formulas(VIII) and (IX) can be produced according to the above-mentioned Methods(1) and (2), using an enantiomer of a compound having an absoluteconfiguration represented by the formula (VII) as a material.

Production of Compound (V) from Compound (III)

The compound (V) can be obtained by reducing compound (III). Thereduction reaction can be carried out according to a method generallyused for reducing lactone to lactol. For example, the reaction iscarried out using a reducing agent (e.g., diisobutylaluminum hydride(DIBAL-H), sodium bis-2-methoxyethoxyaluminum hydride, lithium aluminumtri-t-butoxyhydride and the like, preferably DIBAL-H, lithium aluminumtri-t-butoxyhydride) in a solvent (e.g., dichloromethane, toluene, THF,MTBE and the like, preferably dichloromethane, toluene, THF) at −100° C.to 50° C., preferably −80° C. to 0° C., for 10 min-6 hr, preferably 15min-3 hr.

The amount of the reducing agent to be used is generally 0.8-1.5 mol,preferably 1-1.2 mol, per 1 mol of compound (III). The amount of thesolvent to be used is generally 1-50 L, preferably 2-20 L, per 1 kg ofcompound (III).

The compound (V) can be isolated according to a conventional method. Forisolation, for example, a reaction mixture is poured into a saturatedaqueous ammonium chloride solution, the mixture is partitioned, theobtained organic layer is dried over anhydrous magnesium sulfate and thelike, and filtered, and the solvent is evaporated. The isolate can bepurified by a conventional method but may be used in the next reactionwithout purification.

The compound having a relative configuration represented by the formula(XI) can be produced according to the above-mentioned method using acompound having a relative configuration represented by the formula (IX)as a material.

The compound having an absolute configuration represented by the formula(XI) can be produced according to the above-mentioned method using acompound having an absolute configuration represented by the formula(IX) as a material. The enantiomer of a compound having an absoluteconfiguration represented by the formula (XI) can be produced accordingto the above-mentioned method using an enantiomer of a compound havingan absolute configuration represented by the formula (IX) as a material.

Production of Compound (XIV) from Compound (V)

The compound (XIV) can be obtained by subjecting compound (V) todeprotection and cyclization. For example, compound (V) can bedeprotected and cyclized by reaction in a solvent (e.g., THF,1,4-dioxane, MTBE, di-n-butyl ether, 1,2-dimethoxyethane, toluene andthe like, preferably THF, toluene) using an acid (e.g., hydrochloricacid, sulfuric acid, phosphoric acid, methanesulfonic acid,p-toluenesulfonic acid, strong acidic ion-exchange resin and the like,preferably hydrochloric acid, sulfuric acid) generally at −30° C. to100° C., preferably 0° C. to 40° C. generally for 1 min-24 hr,preferably 1 min-5 hr, more preferably 10 min-3 hr.

The amount of the acid to be used for deprotection and cyclization isgenerally 0.001-10 L, preferably 0.01-2 L, per 1 kg of compound (V). Theamount of the solvent to be used for deprotection and cyclization isgenerally 1-50 L, preferably 2-20 L, per 1 kg of compound (V).

The compound (XIV) can be isolated by a conventional method. Forisolation, for example, after completion of the reaction, the reactionmixture is neutralized with an aqueous alkali solution, partitioned, theobtained organic layer is washed with brine, dried over anhydrousmagnesium sulfate and the like and the solvent is evaporated. Theisolate can be purified by a conventional method.

The compound having a relative configuration represented by the formula(XV) can be produced according to the above-mentioned method using acompound having a relative configuration represented by the formula (XI)as a material.

The compound having an absolute configuration represented by the formula(XV) can be produced according to the above-mentioned method using acompound having an absolute configuration represented by the formula(XI) as a material. The enantiomer of the compound having an absoluteconfiguration represented by the formula (XV) can be produced accordingto the above-mentioned method using an enantiomer of the compound havingan absolute configuration represented by the formula (XI) as a material.

Step (1B)

Production of Compound (IV) from Compound (I)

The compound (IV) can be obtained by protecting hydroxyl group ofcompound (I). The reaction for protecting hydroxyl group variesdepending on the kind of the protecting group, and the hydroxyl group ofcompound (I) can be protected by appropriately determining the reactionconditions and protecting reagent depending on the kind of theprotecting group. For example, when hydroxyl group of compound (I) isprotected with 1-ethoxyethyl group, compound (I) is reacted with ethylvinyl ether, which is a protecting reagent, in a solvent (e.g., THF,MTBE, 1,2-dimethoxyethane, 1,4-dioxane, toluene, dichloromethane and thelike, preferably THF, MTBE, dichloromethane) in the presence of an acid(e.g., p-toluenesulfonic acid, pyridinium p-toluenesulfonate,methanesulfonic acid, sulfuric acid, boron trifluoride, phosphorusoxychloride, acidic ion-exchange resin and the like, preferablyp-toluenesulfonic acid, pyridinium p-toluenesulfonate) generally at −30°C. to 80° C., preferably 0° C. to 40° C. for 10 min-10 hr, preferably 30min-3 hr.

The amount of the protecting reagent, such as ethyl vinyl ether and thelike, to be used is generally 0.8-3 mol, preferably 1-1.5 mol, per 1 molof compound (I). The amount of the acid to be used is generally0.00001-0.2 kg, preferably 0.0001-0.1 kg, per 1 kg of compound (I). Theamount of the solvent to be used is generally 1-50 L, preferably 3-40 L,per kg of compound (I).

The compound (IV) can be isolated by a conventional method. Forisolation, for example, the reaction mixture is neutralized with anaqueous alkali solution, partitioned, the obtained organic layer iswashed with aqueous alkali solution, and the solvent is evaporated. Theisolate can be purified by a conventional method but may be used in thenext reaction without purification.

The compound having a relative configuration represented by the formula(X) can be produced according to the above-mentioned method using acompound having a relative configuration represented by the formula(VII) as a material.

The compound having an absolute configuration represented by the formula(X) can be produced according to the above-mentioned method using acompound having an absolute configuration represented by the formula(VII) as a material. The enantiomer of a compound having an absoluteconfiguration represented by the formula (X) can be produced accordingto the above-mentioned method-using an enantiomer of a compound havingan absolute configuration represented by the formula (VII) as amaterial.

Production of Compound (VI) from Compound (IV)

The compound (VI) can be obtained by reducing compound (IV). Thereduction reaction can be carried out according to a general method usedfor reducing lactone to lactol. For example, the reaction can be carriedout using a reducing agent (e.g., DIBAL-H, sodiumbis-2-methoxyethoxyaluminum hydride, lithium aluminumtri-t-butoxyhydride and the like, preferably DIBAL-H, lithium aluminumtri-t-butoxyhydride) in a solvent (e.g., toluene, THF, MTBE,dichloromethane and the like, preferably toluene, THF) at −100° C. to50° C., preferably −80° C. to 0° C., for 10 min-6 hr, preferably 15min-3 hr.

The amount of the reducing agent to be used is generally 0.8-1.5 mol,preferably 1-1.2 mol, per 1 mol of compound (IV). The amount of thesolvent to be used is generally 1-50 L, preferably 2-20 L, per 1 kg ofcompound (IV).

The compound (VI) can be isolated according to a conventional method.For isolation, for example, saturated aqueous ammonium chloride solutionis added to the reaction mixture, the mixture is dried over anhydrousmagnesium sulfate and the like and filtered, and the solvent isevaporated. The isolate can be purified by a conventional method but maybe used in the next reaction without purification.

The compound having a relative configuration represented by the formula(XII) can be produced according to the above-mentioned method using acompound having a relative configuration represented by the formula (X)as a material.

The compound having an absolute configuration represented by the formula(XII) can be produced according to the above-mentioned method using acompound having an absolute configuration represented by the formula (X)as a material. The enantiomer of a compound having an absoluteconfiguration represented by the formula (XII) can be produced accordingto the above-mentioned method using an enantiomer of a compound havingan absolute configuration represented by the formula (X) as a material.

Production of Compound (XI) from Compound (VI)

The compound (XIV) can be obtained by subjecting compound (VI) todeprotection and cyclization. The reaction conditions vary depending onthe kind of the protecting groups P_(G) and P_(G1). For example, whenthe protecting groups P_(G) and P_(G1) are a benzyl group and a1-ethoxyethyl group, respectively, the benzyl group can be removed byreacting compound (VI) in a solvent (e.g., ethyl acetate, acetic acid,ethanol, methanol, THF, methyl isobutyl ketone and the like, preferablyethyl acetate, THF, ethanol) using a catalyst (e.g., Pd/C, Pd(OH)₂ andthe like, preferably Pd/C) generally at −30° C. to 100° C., preferably0° C. to 60° C., under a hydrogen atmosphere for 15 min-12 hr,preferably 0.5-6 hr.

The amount of the catalyst to be used for removing benzyl group isgenerally 0.0001-0.5 kg per 1 kg of compound (VI) and the amount of thesolvent to be used is generally 0.5-50 L, preferably 2-20 L, per 1 kg ofcompound (VI).

After filtering the catalyst, the solvent is evaporated and the obtainedreaction mixture is reacted in a solvent (e.g., THF, MTBE, ethylacetate, ethanol, methanol, methyl isobutyl ketone, toluene and thelike, preferably THF, ethanol, methanol) using an acid (e.g.,hydrochloric acid, sulfuric acid, methanesulfonic acid,p-toluenesulfonic acid, pyridinium p-toluenesulfonate, acidicion-exchange resin and the like, preferably hydrochloric acid) generallyat −30° C. to 100° C., preferably 0° C. to 60° C. for 10 min-6 hr,preferably 30 min-3 hr, for deprotection of 1-ethoxyethyl group andcyclization.

The amount of the acid to be used for deprotection of 1-ethoxyethylgroup and cyclization is generally 0.001-10 L, preferably 0.01-2 L, per1 kg of compound (VI) and the amount of the solvent to be used isgenerally 1-50L, preferably 2-20 L, per 1 kg of compound (VI).

The compound (XIV) can be isolated by a conventional method. Forisolation, for example, the reaction mixture is neutralized with a basesuch as anhydrous potassium carbonate and the like, after which thesolvent is evaporated. The isolate can be purified by a conventionalmethod.

The compound having a relative configuration represented by the formula(XV) can be produced according to the above-mentioned method using acompound having a relative configuration represented by the formula(XII) as a material.

The compound having an absolute configuration represented by the formula(XV) can be produced according to the above-mentioned method using acompound having an absolute configuration represented by the formula(XII) as a material. The enantiomer of a compound having an absoluteconfiguration represented by the formula (XV) can be produced accordingto the above-mentioned method using an enantiomer of a compound havingan absolute configuration represented by the formula (XII) as amaterial.

Next, other methods relating to the production of compound (I) andcompound (III), which are intermediates for the production method of theabove-mentioned compound (XI), from compound (XIII) are explained indetail. The production methods of compound (I) and compound (III) areshown in the following Scheme 3. Particularly, the production methods ofthe compounds whose absolute configurations are represented by theformula (VII) and the formula (IX) are shown in Scheme 4. As shown inScheme 3, these production methods are characterized by using compound(XIII) as a material and going through compound (XIX) and compound (XX).That is, the present invention is characterized by a method forproducing compound (XIX) using compound (XIII) as a material; a methodfor producing compound (XX) by hydrolysis of compound (XIX); and amethod for producing compound (III) by deprotection of P_(G) and R₃ ofcompound (XX), followed by acetalization or ketalization andlactonization. The above-mentioned methods of the present invention canbe each carried out independently, but it is preferable to combine twoor more of the methods. In the aforementioned method of the presentinvention for production-of compound (I) comprising hydroxyethylation ofcompound (XIII) and then cyclization, it is preferable tohydroxyethylate compound (XIII) to give compound (XIX), hydrolyze theobtained compound (XIX) to give compound (XX), and cyclize the obtainedcompound (XX) to give compound (I). Each method is described in detailin the following.

wherein each symbol is as defined above.

wherein each symbol is as defined above.Production of Compound (XIX) from Compound (XIII)

The compound (XIX) can be obtained by hydroxyethylation of (introductionof R₃O—CH₂CH₂— group wherein R₃ is as defined above into) compound(XIII). For example, compound (XIII) is reacted with a compoundrepresented by the formula: R₃O—CH₂CH₂—X wherein R₃ is as defined aboveand X is a leaving group, with the addition of a base (e.g., lithiumdiisopropylamide, lithium dicyclohexylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide and the like, preferably lithium diisopropylamide).

In the formula: R₃O—CH₂CH₂—X, as the leaving group X, for example,halogen atom (e.g., iodine atom, bromine atom and the like can bementioned), methanesulfonyloxy group, trifluoromethanesulfonyloxy group,p-toluenesulfonyloxy group, benzenesulfonyloxy group and the like can bementioned, and preferably halogen atom, particularly preferably iodineatom, can be mentioned, and as R₃, those similar to the examples of theaforementioned compounds (C), (F) and (XVII)-(XX) can be mentioned, andpreferably benzyl group and t-butyl group can be mentioned. As thecompound represented by the formula: R₃O—CH₂CH₂—X, 2-benzyloxyethyliodide and 2-t-butoxyethyl iodide are preferable.

The amount of the base to be used is generally 0.9-1.5 mol, preferably1.0-1.3 mol, per 1 mol of compound (XIII).

The amount of the compound represented by the formula: R₃O—CH₂CH₂—X tobe used is generally 0.9-2.5 mol, preferably 1.0-1.6 mol, per 1 mol ofcompound (XIII).

The compound (XIX) is produced in a reaction solvent such as THF,hexane, di-n-butyl ether, MTBE, ethylene glycol dimethyl ether,diethylene glycol dimethyl ether, 1,3-dioxolane, 1,4-dioxane, tolueneand the like, preferably THF or hexane. The amount of the reactionsolvent to be used is generally 1-100 L, preferably 3-30 L, per 1 kg ofcompound (XIII).

The reaction temperature is generally −100° C. to 70° C., preferably−80° C. to 40° C., and the reaction time is generally 0.5-48 hr,preferably 3-24 hr.

The compound represented by the formula: R₃O—CH₂CH₂—X can be produced bya known method. For example, 2-benzyloxyethyl iodide can be produced byreacting 2-benzyloxyethanol with methanesulfonyl chloride in thepresence of a catalyst such as triethylamine and the like to give2-benzyloxyethyl methanesulfonate, which is then reacted with sodiumiodide, and 2-t-butoxyethyl iodide can be produced using2-t-butoxyethanol instead of the above-mentioned 2-benzyloxyethanol.

The compound (XIX) can be isolated by a conventional method. Forisolation, for example, the reaction mixture is poured into aqueoushydrochloric acid, the mixture is partitioned, the obtained organiclayer is washed with aqueous alkali solution, and the solvent isevaporated.

When the above-mentioned method is performed using a compoundrepresented by the formula (XVI) as a material, a diastereomer mixturemainly containing a compound having an absolute configurationrepresented by the formula (XVII) (containing a large amount ofanti-form and a small amount of syn-form) can be obtained. When theabove-mentioned method is performed using an enantiomer of a compoundrepresented by the formula (XVI) as a material, a diastereomer mixturemainly containing an enantiomer of a compound having an absoluteconfiguration represented by the formula (XVII) (containing a largeamount of anti-form and a small amount of syn-form) can be obtained.

The diastereomer mixture mainly containing a compound having an absoluteconfiguration represented by the formula (XVII) or a diastereomermixture mainly containing an enantiomer of a compound having an absoluteconfiguration represented by the formula (XVII) is isolated by HPLC togive a pure compound having an absolute configuration represented by theformula (XVII) or a pure enantiomer of a compound having an absoluteconfiguration represented by the formula (XVII). However, thediastereomer mixture may be subjected to a next reaction withoutisolation.

Production of Compound (XX) from Compound (XIX)

The compound (XX) can be obtained by hydrolysis of compound (XIX). Thehydrolysis is performed by, for example, a reaction of compound (XIX)using a base (e.g., potassium hydroxide, sodium hydroxide, lithiumhydroxide and the like, preferably potassium hydroxide) generally at−20° C. to 120° C., preferably 20° C. to 100° C. generally for 0.5-24hr, preferably 1-12 hr.

The amount of the base to be used for hydrolysis is, for example,generally 1-50 mol, preferably 1.2-10 mol, per 1 mol of compound (XIX),when the base is potassium hydroxide.

Hydrolysis is performed in a reaction solvent such as methanol, ethanol,2-propanol, water and the like, preferably in a mixed solvent ofmethanol and water. The amount of the reaction solvent to be used isgenerally 1-100 L, preferably 5-50 L, per 1 kg of compound (XIX).

The compound (XX) can be isolated according to a conventional method.For isolation, for example, after hydrolysis, the reaction mixture isadjusted to generally pH 0-7, preferably pH 0.1-3, using an acid (e.g.,hydrochloric acid, sulfuric acid, phosphoric acid and the like,preferably hydrochloric acid), the solution is partitioned, the obtainedorganic layer is washed with saturated brine, and the solvent isevaporated.

When the above-mentioned method is performed using the diastereomermixture mainly containing a compound having an absolute configurationrepresented by the formula (XVII) (containing a large amount ofanti-form and a small amount of syn-form), which is obtained by theaforementioned method, as a material, a diastereomer mixture mainlycontaining a compound having an absolute configuration represented bythe formula (XVIII) (containing a large amount of anti-form and a smallamount of syn-form) can be obtained. When the above-mentioned method isperformed using the diastereomer mixture mainly containing an enantiomerof a compound having an absolute configuration represented by theformula (XVII) (containing a large amount of anti-form and a smallamount of syn-form) as a material, a diastereomer mixture mainlycontaining an enantiomer of a compound having an absolute configurationrepresented by the formula (XVIII) (containing a large amount ofanti-form and a small amount of syn-form) can be obtained.

When the product from the above-mentioned hydrolysis is obtained as adiastereomer mixture as above, the purity is further increased by addingorganic amine after hydrolysis to give an organic amine salt of compound(XX) and recrystallizing the obtained salt.

As the organic amine to be used, dibenzylamine, benzylamine,dicyclohexylamine, cyclohexylamine, aniline, diethylamine,diisopropylamine, (S)-phenethylamine and the like can be mentioned, withpreference given to dibenzylamine. The amount of the organic amine to beused is generally 0.5-1.5 mol, preferably 0.8-1.3 mol, per 1 mol ofcompound (XX). An organic amine salt is formed in a reaction solventsuch as ethanol, methanol, 2-propanol, 1-propanol, t-butyl alcohol,MTBE, diisopropyl ether, methyl isobutyl ketone, ethyl acetate, waterand the like, preferably ethanol. The amount of the reaction solvent tobe used is generally 1-100 L, preferably 3-30 L, per 1 kg of compound(XX).

The organic amine salt can be produced by heating to generally 20° C. to100° C., preferably 40° C. to 80° C., and then cooling to generally −20°C. to 40° C., preferably −10° C. to 25° C.

The solvent to be used for the recrystallization of the obtained organicamine salt is, for example, ethanol, methanol, 2-propanol, 1-propanol,ethyl acetate, diisopropyl ether, water and the like, preferablyethanol. The amount of the solvent to be used is generally 1-100 L,preferably 3-30 L, per 1 kg of organic amine salt.

A free compound (XX) can be obtained by a conventional method. Forexample, a reaction mixture of the obtained organic amine salt ofcompound (XX) is adjusted to generally pH 0-7, preferably pH 0.5-4,using an acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acidand the like, preferably hydrochloric acid), the mixture is partitioned,the obtained organic layer is washed with saturated brine, and thesolvent is evaporated.

By forming a salt of a diastereomer mixture mainly containing a compoundhaving an absolute configuration represented by the formula (XVIII)(containing a large amount of anti-form and a small amount of syn-form)with an organic amine, a compound having an absolute configurationrepresented by the formula (XVIII), which is configuratively almostpure, and a salt thereof can be obtained highly stereoselectively at asuperior optical purity. By forming a salt of a diastereomer mixturemainly containing an enantiomer of a compound having an absoluteconfiguration represented by the formula (XVIII) (containing a largeamount of anti-form and a small amount of syn-form) with an organicamine, an enantiomer of a compound having an absolute configurationrepresented by the formula (XVIII), which is configuratively almostpure, and a salt thereof can be obtained highly stereoselectively at asuperior optical purity.

Production of Compound (III) from Compound (XX)

The compound (III) can be obtained by deprotection of P_(G) and R₃ ofcompound (XX), and then lactonization, and acetalization or ketalizationthereof. These steps may be performed separately but preferablyperformed simultaneously for convenience. When compound (III) isobtained by simultaneous deprotection of P_(G) and R₃ of compound (XX),lactonization, and acetalization or ketalization of P_(G) and R₃ ofcompound (XX), for example, the reaction is carried out with theaddition of an acetalization reagent or a ketalization reagent (i.e.,diol-protecting reagent) using a catalyst (e.g., in the co-presence ofan acid catalyst such as a strong acidic cation ion-exchange resin(Amberlyst 15(Dry)), phosphoric acid, sulfuric acid, hydrochloric acidand the like, and a reduction catalyst such as palladium-carbon,palladium hydroxide and the like, with preference given to the presenceof a combination of a strong acidic cation ion-exchange resin (Amberlyst15(Dry)) and palladium-carbon) under a hydrogen atmosphere by preferablyadding a dehydrating agent such as anhydrous magnesium sulfate and thelike generally at −20° C. to 100° C., preferably 0° C. to 60° C.,generally for 0.5-24 hr, preferably 1-12 hr.

The acetalization reagent and the ketalization reagent (diol-protectingreagent) vary depending on the kinds of R₄ and R₅ which are protectinggroup constituent elements. For example, when both R₄ and R₅ are methylgroups, 2,2-dimethoxypropane or acetone can be used.

The amount of the acetalization reagent or the ketalization reagent,such as 2,2-dimethoxypropane and the like, is generally 1-30 mol,preferably 1-10 mol, per 1 mol of compound (XX). The amount of thecatalyst to be used is generally 0.1-500 g, preferably 1-250 g, per 1 kgof compound (XX), for both the acid catalyst and the reduction catalyst.This reaction can be carried out using a solvent (e.g., toluene, THF,dichloromethane etc.) or without using a solvent. When a solvent isused, the amount of the solvent to be used is generally 1-50 L,preferably 3-30 L, per 1 kg of compound (XX).

The compound (III) can be isolated according to a conventional method.For isolation, for example, the reaction mixture is filtered, thesolvent is evaporated, an aqueous alkali solution is poured, the mixtureis partitioned and the solvent is evaporated from the obtained organiclayer.

By performing the above-mentioned method using, as a material, acompound having an absolute configuration represented by the formula(XVIII), which is configuratively almost pure and obtained by theaforementioned method, a compound having an absolute configurationrepresented by the formula (IX) can be obtained highly stereoselectivelyat a superior optical purity. In addition, for example, by performingthe aforementioned production method of compound (V) from compound (III)using, as a material, the obtained compound having an absoluteconfiguration represented by the formula (IX), which is highlystereoselective and has a superior optical purity, a compound having anabsolute configuration represented by the formula (XI) can be obtainedhighly stereoselectively at a superior optical purity, and moreover, forexample, by performing the aforementioned production method of compound(XIV) from compound (V) using, as a material, the obtained compoundhaving an absolute configuration represented by the formula (XI), whichis highly stereoselective and has a superior optical purity, a compoundhaving an absolute configuration represented by the formula (XV) can beobtained highly stereoselectively at a superior optical purity. Inaddition, by performing the above-mentioned production method using, asa material, an enantiomer of a compound having an absolute configurationrepresented by the formula (XVIII), which is configuratively almostpure, an enantiomer of a compound having an absolute configurationrepresented by the formula (IX), an enantiomer of a compound having anabsolute configuration represented by the formula (XI) and an enantiomerof a compound having an absolute configuration represented by theformula (XV) can be obtained highly stereoselectively at superioroptical purities.

Production of Compound (I) from Compound (XX)

The compound (I) can be obtained by cyclization of compound (XX). To bespecific, compound (I) can be obtained by lactonization afterdeprotection of R₃ of compound (XX). These steps may be performedseparately but are preferably performed simultaneously for convenience.When compound (I) is obtained by simultaneous deprotection of R₃ andlactonization, for example, the reaction is carried out with theaddition of an acid (e.g., trifluoromethanesulfonic acid,methanesulfonic acid and the like, preferably trifluoromethanesulfonicacid).

The amount of the acid to be used is generally 0.0005-0.5 mol preferably0.05-0.5 mol, per 1 mol of compound (XX).

The compound (I) is produced in a reaction solvent such as THF,1,2-dimethoxyethane, MTBE and the like, preferably THF. The amount ofthe reaction solvent to be used is generally 1-100 L, preferably 3-30 L,per 1 kg of compound (XX).

The reaction temperature is generally −30° C. to 100° C., preferably 0°C. to 60° C., and the reaction time is generally 0.5-96 hr, preferably3-72 hr.

The compound (I) can be isolated according to a conventional method. Forisolation, for example, after evaporation of the solvent of the reactionmixture, aqueous alkali solution is poured, the mixture is partitioned,the obtained organic layer is washed with saturated brine, and thesolvent is evaporated.

By performing the above-mentioned method using, as a material, acompound having an absolute configuration represented by the formula(XVIII), which is configuratively almost pure and obtained by theaforementioned method, a compound having an absolute configurationrepresented by the formula (VII) can be obtained highlystereoselectively at a superior optical purity. In addition, byperforming the above-mentioned method using, as a material, anenantiomer of a compound having an absolute configuration represented bythe formula (XVIII), which is configuratively almost pure, an enantiomerof a compound having an absolute configuration represented by theformula (VII) can be obtained highly stereoselectively at a superioroptical purity.

Other production methods of compound (XV) of the present invention areexplained in detail in the following.

Other production methods of the present invention are characterized by(1) leading compound (XXI) as a starting material to compound (XXII),(2) leading compound (XXII) through compound (XXIV) and compound (XXV)to compound (XXVI), and (3) inverting compound (XXVI) to give compound(XV). That is, the present invention is characterized by a method forproducing compound (XXII) comprising stereoselectively reducing compound(XXI); a method for producing compound (XXIV) comprising a step (2A) forsimultaneous deprotection and introduction of protecting group ofcompound (XXII) as a material to give compound (XXIV), or step (2B) fordeprotection of compound (XXII) to give compound (XXIII) andintroduction of protecting group into the obtained compound (XXIII) togive compound (XXIV); a method for producing compound (XXV) comprisingreducing compound (XXIV); a method for producing compound (XXVI)comprising subjecting compound (XXV) to deprotection and cyclization;and a method for producing compound (XV) comprising inverting hydroxylgroup of compound (XXVI). The above-mentioned methods of the presentinvention can be each performed independently, but it is more preferableto combine two or more of the methods.

(1) Production of Compound (XXII) from Compound (XXI)

The compound (XXI), which is a material, can be obtained by a knownmethod (e.g., method described in JP-A-10-218881 etc.).

The compound (XXII) can be obtained by stereoselective reduction ofcompound (XXI).

As the method of stereoselective reduction, various stereoselectivereduction reactions can be applied, but generally, asymmetrichydrogenation reaction using a transition metal catalyst having anasymmetric ligand is preferable, because it shows a high asymmetricyield, the number of catalyst rotations is large and the like.

Asymmetric hydrogenation reaction using a transition metal catalysthaving an asymmetric ligand is explained in detail in the following.

The compound (XXII) can be produced by, for example, reacting compound(XXI) with hydrogen in a solvent in the presence of a transition metalcatalyst having an asymmetric ligand.

As the asymmetric ligand, for example, optically active phosphinederivative, optically active diamine derivative, optically active aminoalcohol derivative, optically active bisoxazoline derivative, opticallyactive salen derivative and the like can be mentioned. Generally,however, an optically active phosphine derivative is preferable becauseit shows a high asymmetric yield, and the number of catalyst rotationsis large and the like.

As the optically active phosphine derivative, for example, compound(L1)-compound (L6), enantiomers thereof and the like can be mentioned.Of these, compound (L1) and an enantiomer thereof are preferable, andcompound (L1) and an enantiomer thereof, wherein Ra and Rb are phenylgroups and Rc is a hydrogen atom, i.e., optically active BINAP(optically active 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl), moreprecisely, (S)-BINAP and (R)-BINAP which is an enantiomer thereof, aremore preferable, because they can be synthesized easily and can beobtained easily and the like.

In the formulas (L1)-(L6), as the substituents for the optionallysubstituted phenyl, which are represented by Ra, Rb, Rd, Re, Rh, Ri, Rj,Rk, Rl, Rm, Rn and Ro, for example, halogen atom, alkyl, alkoxy and thelike can be mentioned, and halogen atom, alkyl and the like can bepreferably mentioned. The number of the substituents is not particularlylimited, but it is preferably 1-3, which substituents may be the same ordifferent.

In the formulas (L1)-(L6), as the substituents for the optionallysubstituted cyclohexyl, which are represented by Ra, Rb, Rd, Re, Rh, Ri,Rj, Rk, Rl, Rm, Rn and Ro, alkyl (e.g., methyl, ethyl, isopropyl,tert-butyl and the like) and the like can be mentioned, and methyl,tert-butyl and the like can be preferably mentioned. The number of thesubstituents is not particularly limited, but it is preferably 1-3,which substituents may be the same or different.

Of the substituents, halogen atom is exemplified by fluorine atom,chlorine atom, bromine atom and iodine atom, with preference given tochlorine atom and bromine atom.

Of the substituents, alkyl is preferably a straight chain or branchedchain alkyl preferably having 1 to 6, more preferably 1 to 4, carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl andthe like, with preference given to methyl, tert-butyl and the like.

Of the substituents, alkoxy is a straight chain or branched chain alkoxypreferably having 1 to 6, more preferably 1 to 4, carbon atoms, such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, isohexyloxy andthe like, with preference given to methoxy, tert-butoxy and the like.

In the formulas (L1) and (L2), as the halogen atom represented by Rc, Rfand Rg, those mentioned for halogen atom as the above-mentionedsubstituent can be mentioned, with preference given to chlorine atom andbromine atom.

In the formulas (L1) and (L2), as alkyl represented by Rc, Rf and Rg, astraight chain or branched chain alkyl preferably having 1 to 6, morepreferably 1 to 4, carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, isohexyl and the like can be mentioned, withpreference given to methyl, tert-butyl and the like.

In the formulas (L1) and (L2), as alkoxy represented by Rc, Rf or Rg, astraight chain or branched chain alkoxy preferably having 1 to 6, morepreferably 1 to 4, carbon atoms, such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy,isopentoxy, neopentoxy, hexyloxy, isohexyloxy and the like can bementioned, with preference given to methoxy, tert-butoxy and the like.

In the formulas (L1) and (L2), as the substituent for the optionallysubstituted phenyl for Rc, Rf or Rg, those similar to the substituentsof the “optionally substituted phenyl” for the above-mentioned Ra andthe like can be mentioned, with preference given to methyl, tert-butyland the like. The number of the substituents is not particularlylimited, but it is preferably 1-3, which substituents may be the same ordifferent.

The transition metal of the transition metal catalyst is notparticularly limited, and, for example, Group VIII transition metalssuch as ruthenium, rhodium, palladium, iridium, platinum and the likeare preferable, and ruthenium is particularly preferable.

The transition metal catalyst may be one wherein the above-mentioned onekind of asymmetric ligand is coordinated with one transition metal ormay be two or more asymmetric ligands are simultaneously coordinatedwith one transition metal.

The preparation method of a transition metal catalyst having anasymmetric ligand is not particularly limited. For example, a transitionmetal complex formed from an optically active phosphine derivative andruthenium can be mentioned, which is a preferable transition metalcatalyst (hereinafter to be also referred to as a phosphine-rutheniumcomplex) prepared according to a known method, such as a methoddescribed in J. Chem. Soc., Chem. Commun., 922 (1985). To be specific, aruthenium salt or a complex thereof (e.g., benzene ruthenium(II)chloride dimer etc.) is reacted with an optically active phosphinederivative in a solvent to give a phosphine-ruthenium complex. Inaddition, a ruthenium salt or a complex thereof and an optically activephosphine derivative are directly added to a reaction solvent for thereduction reaction to allow for preparation of a phosphine-rutheniumcomplex simultaneously with reduction reaction.

The proportion of the asymmetric ligand and the transition metal is0.3-3 mol, preferably 0.5-2 mol of the transition metal to 1 mol of theasymmetric ligand.

The amount of the transition metal catalyst having an asymmetric ligandto be used is generally 0.00001-0.2 mol, preferably 0.0001-0.1 mol, per1 mol of compound (XXI).

The pressure of hydrogen to be used is generally 0.1-10 MPa, preferably0.3-3 MPa.

As the solvent of the reduction reaction, for example, ethanol,methanol, 2-propanol, 1-propanol, ethyl acetate, acetic acid, DMF andthe like, preferably ethanol, 1-propanol and the like, can be mentioned.The amount of the solvent to be used is generally 1-30 L, preferably3-15 L, per 1 kg of compound (XXI).

The reaction temperature of the reduction reaction is generally 0° C. to150° C., preferably 50° C. to 120° C. While the reaction time depends onthe reagent to be used, reaction temperature, pressure of hydrogen andthe like, the reaction generally ends in 1-24 hr.

The compound (XXII) can be isolated by a conventional method, and, forexample, compound (XXII) can be isolated by pouring the reaction mixtureinto an aqueous sodium hydrogen carbonate solution, extracting themixture with a solvent, partitioning the mixture, washing the organiclayer and removing the catalyst by flash chromatography and the like.The isolate can be purified by a conventional method but may be used inthe next reaction without purification.

In the above-mentioned production method, a compound having an absoluteconfiguration represented by the formula (XXII), and an enantiomerthereof can be produced by selecting the asymmetric ligand. Generally,for example, when compound (L1)-compound (L6) are used as asymmetricligands, a compound having an absolute configuration represented by theformula (XXII), i.e., (1′R,2R)-form, can be produced, and when anenantiomer of compound (L1)-compound (L6) is used as an asymmetricligand, an enantiomer of a compound having an absolute configurationrepresented by the formula (XXII), i.e., (1′S,2S)-form, can be produced.To be specific, for example, when optically active BINAP is used as anasymmetric ligand, a compound having an absolute configurationrepresented by the formula (XXII), i.e., (1′R,2R)-form, can be producedby the use of (S)-BINAP, and an enantiomer of a compound having anabsolute configuration represented by the formula (XXII), i.e.,(1′S,2S)-form, can be produced by the use of (R)-BINAP.

(2) Production of Compound (XXVI) from Compound (XXII)

The compound (XXVI) can be obtained by introducing a protecting groupinto compound (XXII), followed by reduction and cyclization. That is, aprotecting group is introduced into compound (XXII) to give compound(XXIV), and the obtained compound (XXIV) is reduced to give compound(XXV), and the obtained compound (XXV) is subjected to deprotection andcyclization to give compound (XXVI).

Production of Compound (XXIV) from Compound (XXII)

The compound (XXIV) can be produced using compound (XXII) as a materialand by, for example, (2A) a step for deprotection of hydroxyl group ofcompound (XXII) and simultaneous introduction of a protecting group ofdiol to directly give compound (XXIV), or (2B) a step for deprotectionof compound (XXII) to give compound (XXIII), introduction of aprotecting group of diol into the obtained compound (XXIII) to givecompound (XXIV) and the like. Of these, step (2A) is convenient andpreferable.

The method for obtaining compound (XXIV) by simultaneous deprotection ofcompound (XXII) and protection of diol is explained in the following.This method can be performed by simultaneous addition of a deprotectingreagent and a protecting reagent, wherein the reagent is appropriatelydetermined according to the group to be deprotected and the kind of theprotecting group of diol. An example wherein the group to be deprotectedin compound (XXII) is a benzyl group and a diol-protecting group is adimethylmethylene group is explained in the following. However, thepresent invention is not limited at all by this method.

For example, When the protecting group of compound (XXII) is a benzylgroup and the diol-protecting group is a dimethylmethylene group,compound (XXII) and 2,2-dimethoxypropane and/or acetone, which areprotecting reagents, are reacted in a solvent (e.g., THF, ethyl acetateand the like, preferably THF etc.) or without a solvent using a catalyst(e.g., Pd/C, Pd(OH)₂ and the like, preferably Pd/C etc.) and an acidicion-exchange resin (e.g., Amberlyst 15E (manufactured by Rohm & Haas),Nafion SAC13 (manufactured by Dupont) etc.) or an acid (e.g., phosphoricacid, hydrochloric acid, sulfuric acid, methanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonicacid, boron trifluoride, phosphorus oxychloride etc.) generally at −20°C. to 100° C., preferably 0° C. to 50° C., under a hydrogen atmospheregenerally for 0.5-48 hr, preferably 1-24 hr, to give compound (XXIV).

The amount of the protecting reagent such as 2,2-dimethoxypropane andthe like is generally 0.5-100 L, preferably 1-50 L, per 1 kg of compound(XXII). The amount of the reduction catalyst to be used is generally0.0001-0.5 kg per 1 kg of compound (XXII). The amount of the acidicion-exchange resin to be used is generally 0.001-0.5 kg, preferably0.005-0.1 kg, per 1 kg of compound (XXII). When other acid is used, theamount of the acid to be used is generally 0.00001-0.1 kg, preferably0.0001-0.01 kg, per 1 kg of compound (XXII). When a solvent is used, theamount of the solvent to be used is generally 0.5-50 L, preferably1-25L, per 1 kg of compound (XXII).

The compound (XXIV) can be isolated by filtering off the catalyst andevaporating the solvent. The isolate can be purified by a conventionalmethod but may be used in the next reaction without purification.

When R₁₀ is a hydrogen atom and R₁₁ is a lower alkyl group or a phenylgroup, which are the constituent elements of the protecting group, thereaction can be carried out in the same manner as in the above, usingalkanal or benzaldehyde and/or acetal of alkanal or benzaldehyde (e.g.,dimethyl acetal etc.) instead of the above-mentioned2,2-dimethoxypropane or acetone.

When R₁₀ is a lower alkyl group or a phenyl group and R₁₁ is a loweralkyl group or a phenyl group, the reaction can be generally carried outin the same manner as in the above, using R₁₀COR₁₁ and/or acetal thereof(e.g., dimethyl acetal etc.) instead of the above-mentioned2,2-dimethoxypropane or acetone.

When R₁₀ is a lower alkyl group or a phenyl group and R₁₁ is a loweralkoxyl group, the reaction can be carried out in the same manner as inthe above, using trialkyl orthoalkanoate (e.g., MeC(OEt)₃ etc.) ortrialkyl orthobenzoate instead of the above-mentioned2,2-dimethoxypropane or acetone.

When R₁₀ is a hydrogen atom and R₁₁ is a lower alkoxyl group, thereaction can be carried out in the same manner as in the above, usingtrialkyl orthoformate instead of the above-mentioned2,2-dimethoxypropane or acetone.

When R₁₀ and R₁₁ are lower alkoxyl groups, the reaction can be carriedout in the same manner as in the above, using tetraalkyl orthocarbonateinstead of the above-mentioned 2,2-dimethoxypropane or acetone.

The compound having an absolute configuration represented by the formula(XXIV) can be produced according to the above-mentioned method, using acompound having an absolute configuration represented by the formula(XXII) as a material. The enantiomer of the compound having an absoluteconfiguration represented by the formula (XXIV) can be producedaccording to the above-mentioned method, using an enantiomer of acompound having an absolute configuration represented by the formula(XXII) as a material.

Production of Compound (XXV) from Compound (XXIV)

The compound (XXV) can be obtained by reducing compound (XXIV). Thereduction reaction can be carried out according to a method generallyused for reducing lactone to lactol. For example, the reaction iscarried out using a reducing agent (e.g., DIBAL-H, sodiumbis-2-methoxyethoxyaluminum hydride, lithium aluminumtri-t-butoxyhydride and the like, preferably DIBAL-H, lithium aluminumtri-t-butoxyhydride etc.) in a solvent (e.g., dichloromethane, toluene,THF, MTBE and the like, preferably dichloromethane, toluene, THF etc.)at −100° C. to 50° C., preferably −80° C. to 0° C., for 10 min-6 hr,preferably 15 min-3.5 hr.

The amount of the reducing agent to be used is generally 0.8-1.5 mol,preferably 1-1.2 mol, per 1 mol of compound (XXIV). The amount of thesolvent to be used is generally 1-50 L, preferably 2-20 L, per 1 kg ofcompound (XXIV).

The compound (XXV) can be isolated according to a conventional method.For isolation, for example, a reaction mixture is poured into saturatedaqueous ammonium chloride solution, the mixture is partitioned and theobtained organic layer is dried over anhydrous magnesium sulfate and thelike and filtered, and the solvent is evaporated. The isolate can bepurified by a conventional method but may be used in the next reactionwithout purification.

The compound having an absolute configuration represented by the formula(XXV) can be produced according to the above-mentioned method using acompound having an absolute configuration represented by the formula(XXIV) as a material. The enantiomer of a compound having an absoluteconfiguration represented by the formula (XXV) can be produced accordingto the above-mentioned method using an enantiomer of a compound havingan absolute configuration represented by the formula (XXIV) as amaterial.

Production of Compound (XXVI) from Compound (XXV)

The compound (XXVI) can be obtained by subjecting compound (XXV) todeprotection and cyclization. For example, compound (XXV) can bedeprotected and cyclized by a reaction in a solvent (e.g., THF,1,4-dioxane, MTBE, di-n-butyl ether, 1,2-dimethoxyethane, toluene andthe like, preferably THF, toluene etc.) using an acid (e.g.,hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid,p-toluenesulfonic acid, strong acidic ion-exchange resin and the like,preferably hydrochloric acid, sulfuric acid etc.) generally at −30° C.to 100° C., preferably 0° C. to 40° C., generally for 1 min-48 hr,preferably 1 min-24 hr, more preferably 10 min-16 hr.

The amount of the acid to be used for deprotection and cyclization isgenerally 0.001-10 L, preferably 0.01-2 L, per 1 kg of compound (XXV).The amount of the solvent to be used for deprotection and cyclization isgenerally 1-50 L, preferably 2-20 L, per 1 kg of compound (XXV).

The compound (XXVI) can be isolated by a conventional method. Forisolation, for example, after completion of the reaction, the reactionmixture is neutralized with an aqueous alkali solution and partitioned,the obtained organic layer is washed with brine and dried over anhydrousmagnesium sulfate and the like, and the solvent is evaporated. Theisolate can be further purified by a conventional method but may be usedin the next reaction without purification.

The compound having an absolute configuration represented by the formula(XXVI) can be produced according to the above-mentioned method using acompound having an absolute configuration represented by the formula(XXV) as a material. The enantiomer of the compound having an absoluteconfiguration represented by the formula (XXVI) can be producedaccording to the above-mentioned method using an enantiomer of thecompound having an absolute configuration represented by the formula(XXV) as a material.

(3) Production of Compound (XV) from Compound (XXVI)

The compound (XV) can be obtained by inverting the hydroxyl group ofcompound (XXVI). The hydroxyl group can be inverted by, for example, astep (2C) for oxidation to convert compound (XXVI) to compound (XXVII)and reducing the compound to give compound (XV), or a step (2D) forinversion esterification to directly convert compound (XXVI) to compound(XXVIII) and hydrolysis to give compound (XV) and the like.

Step (2C)

Production of Compound (XXVII) from Compound (XXVI)

The compound (XXVII) can be obtained by oxidizing compound (XXVI).

The oxidation reaction can be carried out according to a conventionalmethod used for oxidation of alcohol to ketone. For example, thereaction is carried out using oxalyl chloride and dimethyl sulfoxide inthe presence of a base such as triethylamine and the like in a solvent(e.g., methylene chloride, chlorobenzene, ethyl acetate, tert-butylalcohol and the like, preferably methylene chloride etc.) at −100° C. to50° C., preferably −80° C. to 0° C. for 10 min-12 hr, preferably 30min-5 hr.

The amount of oxalyl chloride to be used is generally 1-4 mol,preferably 1.5-3 mol, per 1 mol of compound (XXVI). The amount ofdimethyl sulfoxide to be used is generally 1-5 mol, preferably 2-4 mol,per 1 mol of compound (XXVI). The amount of the solvent to be used isgenerally 1-100 L, preferably 5-50 L, per 1 kg of compound (XXVI). Theamount of the base, such as triethylamine and the like, to be used isgenerally 3-30 mol, preferably 5-20 mol, per 1 mol of compound (XXVI).

The compound (XXVII) can be isolated according to a conventional method.For isolation, for example, the reaction mixture is poured intosaturated aqueous ammonium chloride solution, the mixture ispartitioned, the obtained organic layer is washed with saturated aqueousammonium chloride solution, and the solvent is evaporated. The isolatecan be purified by a conventional method but may be used in the nextreaction without purification.

Production of Compound (XV) from Compound (XXVII)

The compound (XV) can be obtained by reducing compound (XXVII).

The reduction reaction can be carried out by a conventional method usedfor reducing ketone into alcohol. For example, the reaction can becarried out using a reducing agent (e.g., lithium aluminum hydride,sodium borohydride, lithium borohydride, DIBAL-H and the like,preferably lithium aluminum hydride, sodium borohydride etc.) in asolvent (e.g., THF, MTBE, methanol, ethanol, 2-propanol and the like,preferably THF, methanol, ethanol etc.) at −30° C. to 100° C.,preferably 0° C. to 50° C. for 10 min-12 hr, preferably 30 min-5 hr.

The amount of the reducing agent to be used is generally 0.25-1.5 mol,preferably 0.25-0.75 mol, per 1 mol of compound (XXVII). The amount ofthe solvent to be used is generally 2-100 L, preferably 5-50 L, per 1 kgof compound (XXVII).

The compound (XV) can be isolated according to a conventional method.For isolation, for example, aqueous sodium hydroxide solution is addedto the reaction mixture, the mixture is filtered, washed with THF, thefiltrate is dried over anhydrous magnesium sulfate and the like andfiltered, and the solvent is evaporated. The separated product can bepurified by a conventional method.

Step (2D)

Production of Compound (XXVIII) from Compound (XXVI)

The compound (XXVIII) can be obtained by inversion esterification ofhydroxyl group of compound (XXVI). The inversion esterification isconducted by a reaction of, for example, compound (XXVI) with a compoundrepresented by the formula: R₉OH, wherein R₉ is as defined above, in thepresence of a condensation agent such as triphenylphosphine ortrialkylphosphine (e.g., tricyclohexylphosphine, tributylphosphine,trihexylphosphine, trioctylphosphine and the like, preferablytriphenylphosphine, tricyclohexylphosphine etc.) and azodicarboxylicacid ester (e.g., diethyl azodicarboxylate, diisopropylazodicarboxylate, tert-butyl azodicarboxylate, dimethylazodicarboxylate, dibenzyl azodicarboxylate and the like, preferablydiethyl azodicarboxylate, diisopropyl azodicarboxylate etc.) orazodicarboxylic amide (e.g., 1,1′-azobis(N,N-dimethylformamide),1,1′-(azodicarbonyl)dipiperidine and the like, preferably1,1′-(azodicarbonyl)dipiperidine etc.). For example, the reaction can becarried out using a condensation agent in a solvent (e.g., toluene,xylene, mesitylene, THF, MTBE, 1,2-dimethoxyethane, dichloromethane,chlorobenzene and the like, preferably toluene, xylene, THF etc.) at−20° C. to 100° C., preferably 0° C. to 60° C. for 0.5-48 hr, preferably2-24 hr.

As the compound represented by the formula: R₉OH, for example, benzoicacid, 4-methoxybenzoic acid, 4-nitrobenzoic acid, 3,5-dinitrobenzoicacid, 4-phenylbenzoic acid, acetic acid, formic acid, trifluoroaceticacid and the like, preferably benzoic acid, acetic acid and the like,can be mentioned. The amount of the compound represented by the formula:R₉OH to be used is generally 1-4 mol, preferably 1-2.5 mol, per 1 mol ofcompound (XXVI). The amount of the solvent to be used is generally 2-100L, preferably 5-50 L, per 1 kg of compound (XXVI).

The amount of triphenylphosphine or trialkylphosphine to be used isgenerally 1-4 mol, preferably 1-2.5 mol, per 1 mol of compound (XXVI).The amount of azodicarboxylic acid ester or azodicarboxylic amide to beused is generally 1-4 mol, preferably 1-2.5 mol, per 1 mol of compound(XXVI).

The compound (XXVIII) can be isolated according to a conventionalmethod. For isolation, for example, the reaction mixture is partitioned,the obtained organic layer is washed with water and the solvent isevaporated. The isolate can be purified by a conventional method but maybe used in the next reaction without purification.

Production of Compound (XV) from Compound (XXVIII)

The compound (XV) can be obtained by hydrolysis of compound (XXVIII).

The hydrolysis can be performed by a conventional method using, forexample, a base. The reaction is carried out in the presence of a base(e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide,potassium carbonate, ammonia and the like, preferably sodium hydroxide,potassium carbonate etc.) in a solvent (e.g., methanol, ethanol,2-propanol, water, or a mixed solvent thereof and the like, preferablymethanol, ethanol, a mixed solvent of methanol and water, a mixedsolvent of ethanol and water, etc.) at 0° C. to 80° C., preferably 10°C. to 50° C. for 10 min-24 hr, preferably 0.5 hr-12 hr.

The amount of the base to be used is generally 1-200 mol, preferably2-130 mol, per 1 mol of compound (XXVIII). The amount of the solvent tobe used is generally 1-1000 L, preferably 5-500 L, per 1 kg of compound(XXVIII).

The compound (XV) can be isolated according to a conventional method.For isolation, for example, the solvent of the reaction mixture isevaporated, water is added to the residue, the aqueous layer is washedwith toluene, added with sodium chloride to allow saturation, themixture is partitioned, the organic layer is dried over anhydrousmagnesium sulfate and the like, and the solvent is evaporated. Theisolate can be purified by a conventional method.

The compound having an absolute configuration represented by the formula(XV) can be produced according to the method of the above-mentioned step(2C) or (2D) using a compound having an absolute configurationrepresented by the formula (XXVI) as a material. An enantiomer of thecompound having an absolute configuration represented by the formula(XV) can be produced according to the method of the above-mentioned step(2C) or (2D) using an enantiomer of a compound having an absoluteconfiguration represented by the formula (XXVI) as a material.

EXAMPLES

The present invention is explained in detail by referring to Examples,which are not to be construed as limitative, wherein * shows a relativeconfiguration and (±) shows a racemate.

Example 1

Synthesis of(1′R*,2S*)-2-[2′-(1,1-dimethylethoxy)-1′-hydroxyethyl]-4-butanolide(compound having a relative configuration represented by the formula(VII))

Ethyl 4-t-butoxyacetoacetate (20.0 g) synthesized according to themethod described in Heterocycles 26, 2841 (1987) was dissolved inmethanol (150 mL) and sodium borohydride (1.68 g) was added at atemperature of from 5° C. to 15° C. The mixture was stirred for 1 hr andwater (100 mL) was added. The solvent was mostly evaporated, and theorganic layer extracted twice with MTBE (150 mL) was washed well withwater. MTBE was evaporated to give ethyl(±)-4-t-butoxy-3-hydroxybutanoate (16.9 g). To a solution of lithiumdiisopropylamide 1.5 M cyclohexane solution (73 mL) in THF (100 mL) wasadded a solution of ethyl (±)-4-t-butoxy-3-hydroxybutanoate (10.66 g) inTHF (30 mL) at a temperature of from −58° C. to −48° C. and thetemperature was raised to −20° C. Separately, 2-iodoethanol (21.5 g) andethyl vinyl ether (11.4 g) were mixed in the presence ofp-toluenesulfonic acid monohydrate (10 mg) to give2-(1-ethoxyethoxy)ethyl iodide (19.1 g) and 15.3 g thereof was addeddropwise at a temperature near −20° C. to 0° C. The mixture was stirredovernight at room temperature. The reaction mixture was poured into a 1Naqueous hydrochloric acid (100 mL), MTBE (100 mL) was added and themixture was extracted and washed with saturated aqueous sodium hydrogencarbonate solution. The solvent was evaporated and ethanol (150 mL) andp-toluenesulfonic acid monohydrate (1.3 g) were added to the residue.The mixture was stirred at room temperature for 6 hr. Saturated aqueoussodium hydrogen carbonate solution (20 mL) was added to the reactionmixture and the solvent was mostly evaporated. The residue was extractedwith MTBE (100 mL). The organic layer was washed with saturated aqueoussodium hydrogen carbonate solution (50 mL) and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wassubjected to flash chromatography using heptane/ethyl acetate (3:1) asan eluent to give the title compound (2.0 g) as pale yellow crystals.

¹H-NMR(CDCl₃, δppm): 1.20(3H, s), 2.17-2.28(1H, m), 2.37-2.44(1H, m),2.77-2.82(1H, m), 3.38(1H(—OH), d, J=2 Hz), 3.49(1H, dd, J=9 Hz, J=4Hz), 3.56(1H, dd, J=9 Hz, J=6 Hz), 3.90-3.96(1H, m), 4.22-4.28(1H, m),4.39-4.45(1H, m).

Example 2

Synthesis of (1′R*,2S*)-2-(1′,2′-dihydroxyethyl)-4-butanolide (compoundhaving relative configuration represented by the formula (VIII))

(1′R*,2S*)-2-[2′-(1,1-Dimethylethoxy)-1′-hydroxyethyl]-4-butanolide (1.3g) was added to trifluoroacetic acid (4 mL) and the mixture was stirredon an ice bath for 90 min. Trifluoroacetic acid was evaporated underreduced pressure to give the title compound (1.0 g).

¹H-NMR(CDCl₃, δppm): 2.10-2.20(1H, m), 2.37-2.44(1H, m), 2.80-2.87(1H,m), 3.6-3.8(1H(—OH), br), 3.67(1H, dd, J=12 Hz, J=6 Hz), 3.75(1H, dd,J=12 Hz, J=3 Hz), 3.86-3.90(1H, m), 4.24-4.30(1H, m), 4.43(1H, dt, J=9Hz, J=3 Hz), 4.4-4.5(1H(—OH), br).

Example 3

Synthesis of(2S*,4′R*)-2-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)-4-butanolide(compound having relative configuration represented by the formula (IX))

2,2-Dimethoxypropane (15 mL) was added to(1′R*,2S*)-2-(1′,2′-dihydroxyethyl)-4-butanolide (1.0 g),p-toluenesulfonic acid monohydrate (50 mg) was added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture waspoured into saturated aqueous sodium hydrogen carbonate solution (100mL), extracted twice with MTBE (50 mL). The organic layer was thoroughlywashed with saturated aqueous sodium hydrogen carbonate solution, andthe solvent was evaporated to give the title compound (0.75 g).

¹H-NMR(CDCl₃, δppm): 1.36(3H, s), 1.42(3H, s), 2.18-2.28(1H, m),2.37-2.47(1H, m), 2.88-2.95(1H, m), 3.97(1H, dd, J=9 Hz, J=6 Hz),4.08(1H, dd, J=9 Hz, J=7 Hz), 4.19-4.36(1H, m), 4.37-4.45(1H, m),4.45-4.49(1H, m).

Example 4

Synthesis of(3S*,4′R*)-3-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)tetrahydrofuran-2-ol(compound having relative configuration represented by the formula (XI))

(2S*,4′R*)-2-(21,2′-Dimethyl-[11,31]dioxolane-4′-yl)-4-butanolide (400mg) was dissolved in dichloromethane (4 mL), and DIBAL-H 1.0 M toluenesolution (2.4 mL) was added at around −78° C. The mixture was stirred atsaid temperature for 1 hr. The reaction mixture was poured intosaturated aqueous ammonium chloride solution (2 mL) and extracted withMTBE (7.5 mL). The organic layer was dried over anhydrous magnesiumsulfate, and a small amount of a filtering aid (celite, manufactured byCelite Corporation) was added. The mixture was filtrated and the solventwas evaporated to give the title compound (340 mg).

¹H-NMR(CDCl₃, δppm): 1.35(3H, s), 1.44(3H, s), 1.45-1.58(1H, m),1.78-1.85(1H, m), 2.08-2.35(2H, m), 3.62-3.72(1H, m), 3.86-4.08(3H, m),4.10-4.17(0.5H, s), 4.27-4.33(0.5H, m).

Example 5

Synthesis of (3R*,3aS*,6aR*)-hexahydrofuro[2,3-b]furan-3-ol (compoundhaving a relative configuration represented by the formula (XV))

(3S*,4′R*)-3-(2′,2′-Dimethyl-[1′,3′]dioxolane-4′-yl)tetrahydrofuran-2-ol(120 mg) was dissolved in THF (2 mL), and 6N hydrochloric acid (0.1 mL)was added. The mixture was stirred at room temperature for 20 min. 10%Aqueous sodium hydrogen carbonate solution (2 mL) was added to thereaction mixture and the mixture was extracted with ethyl acetate (2mL). After washing with 10% brine (2 mL), the extract was dried overanhydrous magnesium sulfate and the solvent was evaporated to give thetitle compound (50 mg). ¹H-NMR did not show a peak of stereoisomer.

¹H-NMR(CDCl₃, δppm): 1.73(1H(—OH), d, J=6 Hz), 1.82-1.93(1H, m),2.28-2.34(1H, m), 2.82-2.89(1H, m), 3.65(1H,dd, J=9 Hz, J=7 Hz),3.88-3.94(1H, m), 3.97-4.02(2H, m), 4.42-4.49(1H, m), 5.70(1H, d, J=5Hz).

Example 6

Synthesis of (1′R*,2S*)-2-[2′-benzyloxy-1′-hydroxyethyl]-4-butanolide(compound having a relative configuration represented by the formula(VII))

Ethyl 4-benzyloxyacetoacetate (42.1 g) synthesized according to themethod describe in U.S. Pat. No. 5,399,722 was dissolved in methanol(300 mL) and sodium borohydride (3.03 g) was added at a temperature offrom 5° C. to 10° C. The mixture was stirred for 1 hr and water (300 mL)was added. The solvent was mostly evaporated, and the organic layerextracted twice with MTBE (30b mL) was washed twice with 2% sodiumhydrogen carbonate (100 mL) and washed twice with saturated brine (150mL), dried over anhydrous magnesium sulfate and filtrated. MTBE wasevaporated to give ethyl (±)-4-benzyloxy-3-hydroxybutanoate (38.8 g). Toa solution of lithium diisopropylamide 1.5 M cyclohexane solution (190mL) in THF (200 mL) was added a solution of ethyl(±)-4-benzyloxy-3-hydroxybutanoate (29.4 g) in THF (50 mL) at atemperature of from −78° C. to −60° C. and the temperature was raised to−20° C. Separately, 2-iodoethanol (34.4 g) and ethyl vinyl ether (23.1g) were mixed in the presence of p-toluenesulfonic acid monohydrate (20mg) to give 2-(1-ethoxyethoxy)ethyl iodide (47.9 g) and 39.3 g thereofwas added dropwise at a temperature near −20° C. to 0° C. The mixturewas stirred overnight at room temperature. The reaction mixture waspoured into a 1N aqueous hydrochloric acid (450 mL), and the mixture wasextracted twice with MTBE (200 mL) and washed with saturated aqueoussodium hydrogen carbonate solution. The solvent was evaporated andmethanol (300 mL) and p-toluenesulfonic acid monohydrate (5.3 g) wereadded to the residue. The mixture was stirred at room temperature for 6hr. Triethylamine (2.0 g) was added to the reaction mixture and thesolvent was mostly evaporated. The residue was extracted with ethylacetate (300 mL). The organic layer was washed with water (150 mL) andsaturated aqueous sodium hydrogen carbonate solution (150 mL) and driedover anhydrous magnesium sulfate. The solvent was evaporated.Diisopropyl ether (120 mL) was added to the residue and the mixture wasrecrystallized to give the title compound (5.65 g) (yellow finecrystals). The peak of syn-form (1′R*,2R*-body) was not detected in NMRand HPLC under the following conditions.

¹H-NMR(CDCl₃, δppm): 2.06-2.17(1H, m), 2.27-2.33(1H, m), 2.78-2.85(1H,m), 3.62(1H(—OH), br), 3.61-3.67(2H, m), 3.97-4.01(1H, m), 4.18-4.24(1H,m), 4.39(1H, dt, J=9 Hz, J=3 Hz), 4.55(1H, d, J=12 Hz), 4.63(1H, d, J=12Hz), 7.26-7.37(5H, m).

HPLC conditions: Daicel Chiralcel OD-H (0.46 cmφ×25 cm, 9/1hexane/2-propanol; 1 ml/min, 254 nm) syn-(1′R,2R) t_(r)=15 min;syn-(1′S,2S) t_(r)=17 min; anti-(1′R,2S) or anti-(1′S,2R) t_(r)=19 minor t_(r)=24 min.

Example 7

Synthesis of (1′R*,2S*)-2-(1′,2′-dihydroxyethyl)-4-butanolide (compoundhaving relative configuration represented by the formula (VIII))

(1′R*,2S*)-2-(2′-Benzyloxy-1′-hydroxyethyl)-4-butanolide (2.00 g) wasdissolved in ethyl acetate (30 mL) and 10% Pd/C (manufactured by N.E.Chemcat, 50% Wet PE-Type) (200 mg) was added. The mixture was stirredunder atmospheric pressure of hydrogen at around 25° C. for 3 hr. Thecatalyst was filtered off and the solvent was evaporated to give thetitle compound (1.27 g). The spectrum data thereof were the same asthose of Example 2.

Example 8

Synthesis of(1′R*,2S*)-2-[2′-benzyloxy-1′-(1″-ethoxyethoxy)ethyl]-4-butanolide(compound having relative configuration represented by the formula (X))

(1′R*,2S*)-2-(2′-Benzyloxy-1′-hydroxyethyl)-4-butanolide (1.00 g) wasdissolved in a mixed solvent of THF (10 mL) and MTBE (20 mL) andp-toluenesulfonic acid monohydrate (60 mg) was added. Then, ethyl vinylether (1.1 g) was added dropwise. The reaction mixture was stirred atroom temperature for 3 hr. The mixture was poured into saturated aqueoussodium hydrogen carbonate solution, extracted with MTBE and washed wellwith saturated aqueous sodium hydrogen carbonate solution. The solventwas evaporated to give the title compound (1.24 g).

¹H-NMR(CDCl₃, δppm): 1.15(1.5H, t, J=7 Hz), 1.19(1.5H, t, J=7 Hz),1.29(1.5H, d, J=6 Hz), 1.31(1.5H, d, J=6 Hz), 2.17-2.37(2H, m),2.92-2.98(1H, m), 3.42-3.62(2H, m), 3.70-3.78(2H, m), 4.08-4.37(3H, m),4.54(2H, s), 4.82(1H, q, J=5 Hz), 7.26-7.36(5H, m).

Example 9

Synthesis of(1′R*,3S*)-3-[2′-benzyloxy-1′-(1′′-ethoxyethoxy)ethyl]tetrahydrofuran-2-ol(compound having relative configuration represented by the formula(XII))

(1′R*,2S*)-2-[2′-Benzyloxy-1′-(1′′-ethoxyethoxy)ethyl]-4-butanolide(1.22 g) was dissolved in toluene (10 mL), and a solution (4.4 mL) ofDIBAL-H (1.0 M) in toluene was added at around −78° C. The mixture wasstirred at the same temperature for 1 hr. Saturated aqueous ammoniumchloride solution (5 mL) was added to the reaction mixture, and afteradding anhydrous magnesium sulfate, the mixture was filtered through afiltering aid (celite, manufactured by Celite Corporation). The solventwas evaporated to give the title compound (1.23 g).

¹H-NMR(CDCl₃, δppm): 1.11-1.24(3H, m), 1.31(3H, d, J=5 Hz),1.62-1.83(2H, m), 2.00-2.08(0.5H, m), 2.20-2.38(0.5H, m),2.40-2.51(0.5H, m), 2.63-2.80(0.5H, m), 3.44-4.21(7H, m), 4.48-4.61(2H,m), 4.75-4.91(1H, m), 5.39-5.53(1H, m), 7.26-7.36(5H, m).

Example 10

Synthesis of (3R*,3aS*,6aR*)-hexahydrofuro[2,3-b]furan-3-ol (compoundhaving a relative configuration represented by the formula (XV))

(1′R*,3S*)-3-[2′-Benzyloxy-1′-(1″-ethoxyethoxy)ethyl]tetrahydrofuran-2-ol(1.22 g) was dissolved in ethyl acetate (20 mL), and 10% Pd/C(manufactured by N. E. Chemcat, 50% Wet PE-Type) (242 mg) was added. Themixture was stirred under atmospheric pressure of hydrogen at around 25°C. for 1 hr. The catalyst was filtered off, and the solvent wasevaporated. THF (10 mL) and 6N hydrochloric acid (0.05 mL) were addedand stirred at around 25° C. for 1 hr. Anhydrous potassium carbonate wasadded to the reaction mixture and the solvent was evaporated to give thetitle compound (0.49 g). The spectrum data of this compound were thesame as those in Example 5.

Example 11

Synthesis of(2S*,4′R*)-2-(2-,2′-dimethyl-[1′,3′]dioxolane-4′-yl)-4-butanolide(method for directly synthesizing compound (IX) from compound (VII))

(1′R*,12S*)-2-(2′-Benzyloxy-1′-hydroxyethyl)-4-butanolide (97 mg) wasdissolved in acetone (2.5 mL), and 2,2-dimethoxypropane (0.5 mL), 10%Pd/C (manufactured by N. E. Chemcat, 50% Wet PE-Type) (48 mg) andion-exchange resin (Amberlyst 15E(Dry), manufactured by Rohm & Haas) (1mg) were added. The mixture was stirred under atmospheric pressure ofhydrogen at around 25° C. for 2 hr. After filtering off the catalyst,the solvent was evaporated to give the title compound (70 mg). Thespectrum data of this compound were the same as those in Example 3.

Example 12

Synthesis of (3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol

In the same manner as in Example 6 and using ethyl(S)-4-benzyloxy-3-hydroxybutanoate that can be synthesized according tothe method described in, for example, U.S. Pat. No. 5,399,722 instead ofethyl (±)-4-benzyloxy-3-hydroxybutanoate,(1′S,2R)-2-[2′-benzyloxy-1′-hydroxyethyl]-4-butanolide can be produced,by subsequently performing Example 7,(1′S,2R)-2-(1′,2′-dihydroxyethyl)-4-butanolide can be produced, bysubsequently performing Example 3,(2R,4′S)-2-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)-4-butanolide can beproduced, by subsequently performing Example 4,(3R,4′S)-3-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)tetrahydrofuran-2-olcan be produced, and by subsequently performing Example 5,(3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol can be produced.

Example 13

Synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol

In the same manner as in Example 1 and using ethyl(R)-4-t-butoxy-3-hydroxybutanoate that can be synthesized according tothe method described in, for example, Heterocycles 26, 2841 (1987)instead of ethyl (±)-4-t-butoxy-3-hydroxybutanoate,(1′R,2S)-2-[2′-(1,1-dimethylethoxy)-1′-hydroxyethyl]-4-butanolide can beproduced, by subsequently performing Example 2,(1′R,2S)-2-(1′,2′-dihydroxyethyl)-4-butanolide can be produced, bysubsequently performing Example 3,(2S,4′R)-2-(2′1,2′-dimethyl-[1′,3′]dioxolane-4′-yl)-4-butanolide can beproduced, by subsequently performing Example 4,(3S,4′R)-3-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)tetrahydrofuran-2-olcan be produced, and by subsequently performing Example 5,(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol can be produced.

Reference Example 1

Synthesis of 2-benzyloxyethyl Iodide

2-Benzyloxyethanol (85.0 g) and triethylamine (73.5 g) were dissolved inTHF (500 mL) and methanesulfonyl chloride (76.8 g) was added dropwise atfrom 0° C. to 10° C. The mixture was stirred for 3 hr. 10% Aqueoussodium bicarbonate (300 mL) was poured into the reaction mixture, themixture was partitioned and combined with an extract of the aqueouslayer with MTBE (300 mL), and the mixture was washed with 10% aqueoussodium bicarbonate and saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated to give 2-benzyloxyethylmethanesulfonate (124.0 g). The 2-benzyloxyethyl methanesulfonate (124.0g) was dissolved in acetone (500 mL), and sodium iodide (130.0 g) wasadded. The mixture was stirred at from 50° C. to 60° C. for 3 hr. Thereaction mixture was filtered and the solvent was evaporated. Water (300mL) was added, and the mixture was extracted twice with toluene (300mL). The toluene layer was washed successively with aqueous sodiumhydrogen sulfite solution, water and brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated to give the title compound(127.0 g).

Example 14

Synthesis of ethyl(2S-3R)-4-benzyloxy-3-hydroxy-2-(2′-benzyloxyethyl)butanoate (compoundrepresented by the formula (XVII))

Under a nitrogen stream, THF (140 mL) was added to diisopropylamine(20.9 g) and thereto was added a solution (120 mL) of 15 wt %n-butyllithium in hexane at from −60° C. to −65° C. Furthermore, ethyl(R)-4-benzyloxy-3-hydroxybutanoate (20.0 g) (99% ee or above) that canbe synthesized according to the method described in U.S. Pat. No.5,399,722 was added dropwise at from −55° C. to −65° C. The reactionmixture was warmed to −25° C. and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (60 g) was added.Then, 2-benzyloxyethyl iodide (27 g) synthesized according to ReferenceExample 1 was added dropwise at around −15° C. The reaction mixture wasstirred at from −15° C. to −10° C. for 23 hr and 2 mol/L aqueoushydrochloric acid (160 mL) was added. The mixture was extracted twicewith toluene (300 mL) and washed with 10% aqueous sodium bicarbonate.The solvent was evaporated to give a mixture (35.9 g) containing thetitle compound and a diastereomer thereof, ethyl(2R,3R)-4-benzyloxy-3-hydroxy-2-(2′-benzyloxyethyl)butanoate, at a ratioof 3:1. A part was isolated by preparative HPLC to give a pure titlecompound.

NMR spectrum of ethyl(2S,3R)-4-benzyloxy-3-hydroxy-2-(2′-benzyloxyethyl)butanoate

¹H-NMR(CDCl₃, δppm): 1.19(3H, t, J=7 Hz), 1.84-1.92(1H, m),2.00-2.10(1H, m), 2.78-2.83(1H, m), 3.43-3.57(4H, m), 3.89-3.95(1H, m),4.08(2H, q, J=7 Hz), 4.47(2H, s), 4.53(2H, s), 7.24-7.36(10H, m).

Example 15

Synthesis of (2S,3R)-4-benzyloxy-3-hydroxy-2-(2′-benzyloxyethyl)butanoicacid (compound represented by the formula (XVIII) or a salt thereof)

The mixture (27.0 g) containing ethyl(2S,3R)-4-benzyloxy-3-hydroxy-2-(2′-benzyloxyethyl)butanoate and adiastereomer thereof, ethyl(2R,3R)-4-benzyloxy-3-hydroxy-2-(2′-benzyloxyethyl)butanoate, at a ratioof 3:1 was dissolved in methanol (200 mL), and 10% aqueous potassiumhydroxide solution (57.8 g) was added. The mixture was heated at 60° C.for 2 hr. Water (600 mL) was added to the reaction mixture and themixture was washed with toluene (200 mL), adjusted to pH 1 with 2 mol/Laqueous hydrochloric acid and extracted 3 times with toluene (300 mL).The toluene layer was washed with saturated brine (300 mL), concentratedand to the residue was added ethanol (100 mL). The solution was heatedto 65° C. and dibenzylamine (27.0 g) was added. The salt obtained bycooling was recrystallized from ethanol (273 mL) and furtherrecrystallized from ethanol (77 mL) to give a dibenzylamine salt (17.7g) of the title compound (99% de or above). NMR spectrum ofdibenzylamine salt

¹H-NMR(CDCl₃, δppm): 1.89-2.07(2H, m), 2.67-2.72(1H, m), 3.48-3.60(4H,m), 3.78(4H, s), 3.87-3.91(1H, m), 4.46(2H, s), 6.4-6.7(3H, br),7.22-7.36(20H, m).

This compound (17.5 g) was adjusted to not higher than pH 1 with 2 mol/Lhydrochloric acid (100 mL), and the aqueous layer was extracted withtoluene (150 mL), and further 3 times with 100 mL, washed with saturatedbrine and concentrated to give the title compound (9.4 g).

¹H-NMR(CDCl₃, δppm): 1.86-1.97(1H, m), 1.99-2.08(1H, m), 2.81-2.86(1H,m), 3.50-3.61(4H, m), 3.97-4.01(1H, m), 4.49(2H, s), 4.53(2H, s),7.24-7.35(10H, m).

specific optical rotation [α]_(D) ²⁶ −3.50° (C=4.0, MeOH)

Example 16

Synthesis of(2S,4′R)-2-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)-4-butanolide(compound represented by the formula (IX))

(2S,3R)-4-Benzyloxy-3-hydroxy-2-(2′-benzyloxyethyl)butanoic acid (8.36g) was dissolved in 2,2-dimethoxypropane (80 mL), and reacted withanhydrous magnesium sulfate (1.4 g), Amberlyst 15(Dry) (1.3 g) and 10%palladium-carbon (1.7 g) under atmospheric pressure of hydrogen for 3hr. The reaction mixture was filtered and the solvent was evaporated.10% Aqueous sodium bicarbonate (200 mL) was added and the mixture waswashed with heptane (100 mL) and extracted 3 times with ethyl acetate(200 mL). The organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated to give the title compound (3.0 g).

The spectrum data of this compound were the same as those in Example 3.

specific optical rotation [α]_(D) ²⁸+16.4° (C=4.0, MeOH)

Example 17

Synthesis of(3S,4′R)-3-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)tetrahydrofuran-2-ol(compound represented by the formula (XI))

(2S,4′R)-2-(2′,2′-Dimethyl-[1′,3′]dioxolane-4′-yl)-4-butanolide (2.7 g)was dissolved in toluene (30 mL) and cooled to −78° C. 1.0 M DIBAL-Htoluene solution (16 mL) was added, and the mixture was stirred at thesame temperature for 2 hr. Saturated aqueous ammonium chloride solution(25 mL) and MTBE (20 mL) were added to the reaction mixture, anhydrousmagnesium sulfate (10 g) and celite (5 g) were added, and the mixturewas filtered. The residue was thoroughly extracted with ethyl acetateand combined with the filtrate. The solvent was evaporated to give thetitle compound (2.4 g).

The NMR spectrum of this compound was the same as that in Example 4.

Example 18

Synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (compoundrepresented by the formula (XV))

(3S,4′R)-3-(2′,2′-Dimethyl-[1′,3′]dioxolane-4′-yl)tetrahydrofuran-2-ol(2.4 g) was dissolved in THF (20 mL), and 2 mol/L hydrochloric acid (3.2mL) was added. The mixture was stirred at room temperature for 16 hr.Water (30 mL) and sodium hydrogen carbonate (5 g) were added to thereaction mixture, and the mixture was washed twice with heptane (15 mL).Sodium chloride was added to the aqueous layer to saturation and themixture was extracted 10 times with ethyl acetate (50 mL). Ethyl acetatewas concentrated to give an almost pure title compound (1.4 g).

The NMR spectrum data of this compound were the same as those in Example5.

specific optical rotation [α]_(D) ²⁶−12.0° (C=5.6, MeOH)

Example 19

Synthesis of ethyl(2S,3R)-4-benzyloxy-3-hydroxy-2-[2′-(1,1-dimethylethoxy)ethyl]butanoate(compound represented by the formula (XVII))

Under a nitrogen stream, THF (200 mL) was added to diisopropylamine(23.4 g). To the resulting solution was added a solution (140 mL) of 15wt % n-butyllithium in hexane at from −60° C. to −65° C. Further, ethyl(R)-4-benzyloxy-3-hydroxybutanoate (25.0 g) (99% ee or above) that canbe synthesized by the method described in U.S. Pat. No. 5,399,722 wasadded dropwise at from −55° C. to −65° C. The reaction mixture waswarmed to −25° C. and 2-t-butoxyethyl iodide (26.4 g) synthesizedaccording to Reference Example 1 using 2-t-butoxyethanol as a materialinstead of 2-benzyloxyethanol was added dropwise at around −20° C. Thereaction mixture was stirred at room temperature for 24 hr, 2 mol/Laqueous hydrochloric acid (200 mL) was added, and the mixture wasextracted twice with MTBE (250 mL) and washed with 10% aqueous sodiumbicarbonate. The solvent was evaporated to give a mixture (35.9 g)containing the title compound and a diastereomer thereof, ethyl(2R,3R)-4-benzyloxy-3-hydroxy-2-[2′-(1,1-dimethylethoxy)ethyl]butanoate,at a ratio of about 3:1. A part thereof was isolated by preparative HPLCto give a pure title compound.

NMR spectrum of ethyl(2S,3R)-4-benzyloxy-3-hydroxy-2-[2′-(1,1-dimethylethoxy)ethyl]butanoate

¹H-NMR(CDCl₃, δppm): 1.15(3H, s), 1.23(3H, t, J=7 Hz), 1.74-1.82(1H, m),1.93-2.02(1H, m), 2.76-2.81(1H, m), 3.30-3.62(4H, m), 3.90-3.98(1H, m),4.11(2H, q, J=7 Hz), 4.54(2H, s), 7.24-7.35(5H, m).

Example 20

Synthesis of(2S,3R)-4-benzyloxy-3-hydroxy-2-[2′-(1,1-dimethylethoxy)ethyl]butanoicacid (compound represented by the formula (XVIII) or a salt thereof)

A mixture (10.3 g) containing ethyl(2S,3R)-4-benzyloxy-3-hydroxy-2-[2′-(1,1-dimethylethoxy)ethyl]butanoateand a diastereomer thereof, ethyl(2R,3R)-4-benzyloxy-3-hydroxy-2-[2′-(1,1-dimethylethoxy)ethyl]butanoate,at a ratio of about 3:1 was dissolved in methanol (30 mL), and 20%aqueous potassium hydroxide solution (13 g) was added. The mixture washeated at 60° C. for 2 hr. Methanol was evaporated and water (200 mL)was added and the mixture was washed twice with toluene (100 mL), andadjusted to pH 1 with 2 mol/L aqueous hydrochloric acid. The mixture wasextracted twice with toluene (100 mL). The toluene layer was washed withsaturated brine (100 mL), concentrated and to the concentrated residuewas added methanol (18 mL). The solution was heated to 65° C.,dibenzylamine (4.2 g) was added and the mixture was cooled to give asalt, which was recrystallized from ethanol (25 mL) and furtherrecrystallized from ethanol (77 mL), (60 mL) to give a dibenzylaminesalt (2.03 g) of the title compound (99% de or above). This compound(2.0 g) was adjusted to not higher than pH 1 with 2 mol/L hydrochloricacid (10 mL) and the aqueous layer was extracted with toluene (20 mL),(50 mL), washed with saturated brine and concentrated to give the titlecompound (1.2 g).

Example 21

Synthesis of (1′R,2S)-2-[2′-benzyloxy-1′-hydroxyethyl]-4-butanolide(compound represented by the formula (VII))

(2S,3R)-4-Benzyloxy-3-hydroxy-2-[2′-(1,1-dimethylethoxy)ethyl]butanoicacid (0.80 g) was dissolved in THF (10 mL) and trifluoromethanesulfonicacid (122 mg) was added. The mixture was stirred at room temperature for3 days. The solvent was evaporated from the reaction mixture, theresidue was washed with heptane (100 mL) and extracted with 10% aqueoussodium bicarbonate (100 mL), (200 mL) into the aqueous layer. Theaqueous layer was extracted 3 times with ethyl acetate (100 mL), washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated to give the title compound (0.37 g) as paleyellow crystals.

The NMR spectrum of this compound was the same as that in Example 6.

Only a peak corresponding to anti-(1′R,2S)-form was found under the HPLCconditions using the optically active column of Example 6, and the peaksof other isomers were below detection level.

Example 22

Synthesis of (1′R,2R)-2-[2′-benzyloxy-1′-hydroxyethyl]-4-butanolide(compound (XXII))

2-Benzyloxyacetyl-γ-butyrolactone (29.7 g) that can be synthesizedaccording to the method described in JP-A-10-218881 was dissolved inethanol (300 mL) and a solution of benzene ruthenium(II) chloride dimer(318 mg) and (S)-(−)-BINAP (791 mg) in DMF (30 mL) was reacted under ahydrogen atmosphere at 500 kPa, 100° C. for 3 hr. The reaction mixturewas poured into 5% aqueous sodium hydrogen carbonate solution, extractedwith ethyl acetate, and washed with brine. The catalyst was removed byflash chromatography to give an isomer mixture (23.5 g) mainlycontaining the title compound. The syn:anti diastereomer ratio of theobtained compound was 11:2, and the optical purity of the syn-form(1′R,2R-form) was 78% ee. Syn-form: ¹H-NMR(CDCl₃, δppm): 2.14-2.22(1H,m), 2.33-2.43(1H, m), 2.73(1H, dt, J=10 Hz, J=4 Hz), 2.79(1H(—OH), d,J=5 Hz), 3.55(2H, d, J=6 Hz), 4.16-4.23(1H, m), 4.28-4.33(1H, m),4.36(1H, dt, J=9 Hz, J=3 Hz), 4.54(1H, d, J=12 Hz), 4.57(1H, d, J=12Hz), 7.26-7.38(5H, m).

HPLC condition: Daicel Chiralcel OD-H (0.46 cmφ×25 cm, 9/1hexane/2-propanol; 0.8 ml/min, 254 nm) syn-(1′R,2R) t_(r)=16 min;syn-(1′S,2S) t_(r)=19 min; anti-(1′R,2S) or anti-(1′S,2R) t_(r)=21 minor t_(r)=26 min.

Example 23

Synthesis of(2R,4′R)-2-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)-4-butanolide(compound (XXIV))

(1′R,2R)-2-(2′-Benzyloxy-1′-hydroxyethyl)-4-butanolide (23.5 g) obtainedin Example 22 was dissolved in acetone (150 mL), and2,2-dimethoxypropane (40 mL), 10% Pd/C (manufactured by N. E. Chemcat,50% Wet PE-Type) (3.0 g) and Amberlyst 15E(Dry) (0.94 g) were added. Themixture was stirred under an atmospheric pressure of hydrogen for 22 hr.After filtering off the catalyst, the solvent was evaporated to give thetitle compound (17.7 g).

¹H-NMR(CDCl₃, δppm): 1.36(3H, s), 1.42(3H, s), 2.28-2.44(2H, m),2.68-2.74(1H, m), 3.85(1H, dd, J=9 Hz, J=6 Hz), 4.22(1H, dd, J=9 Hz, J=6Hz), 4.26-4.30(1H, m), 4.35-4.44(2H, m).

Example 24

Synthesis of(3R,4′R)-3-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)tetrahydrofuran-2-ol(compound (XXV))

(2R,4′R)-2-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)-4-butanolide (17.7 g)obtained in Example 23 was dissolved in THF (150 mL) and a solution (100mL) of DIBAL-H 1.0 M in toluene was added at around −70° C. The mixturewas stirred at the same temperature for 3.5 hr. The reaction mixture waspoured into saturated aqueous ammonium chloride solution (120 mL) andextracted with MTBE (100 mL). The organic layer was dried over anhydrousmagnesium sulfate, and after adding a small amount of filtering aid(celite), filtered. The solvent was evaporated to give the titlecompound (13.8 g).

¹H-NMR(CDCl₃, δppm): 1.36, 1.37(total 3H, each s), 1.43, 1.44(total 3H,each s), 1.82-1.93, 2.03-2.43(total 3H, each m), 3.15-3.43(1H, —OH, br),(1H, m), 3.62-3.71(1H, m), 3.84-4.43(4H, m), 5.24-5.26, 5.33-5.36(total1H, each m).

Example 25

Synthesis of (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (compound(XXVI))

(3R,4′R)-3-(2′,2′-Dimethyl-[1′,3′]dioxolane-4′-yl)tetrahydrofuran-2-ol(13.8 g) obtained in Example 24 was dissolved in THF (120 mL), and 6Nhydrochloric acid (4 mL) was added. The mixture was stirred overnight atroom temperature. Anhydrous potassium carbonate (25 g) was added to thereaction mixture and the mixture was filtered. The concentrated residuewas dissolved in toluene (20 mL) with heating and diisopropyl ether (30mL) was added. The mixture was stirred at room temperature and theresulting crystals were collected by filtration and dried to give thetitle compound (2.8 g, 88% ee), which was almost a pure syn-form.

¹H-NMR(CDCl₃, δppm): 1.67-1.75(1H, m), 1.95-2.05(1H (—OH), br),2.13-2.23(1H, m), 2.79-2.84(1H, m), 3.81-3.91(3H, m), 3.98(1H, dd, J=10Hz, J=3 Hz), 4.23(1H, d, J=3 Hz), 5.89(1H, d, J=5 Hz).

Example 26

Synthesis of (3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl benzoate(compound (XXVIII))

(3R,3aR,6aS)-Hexahydrofuro[2,3-b]furan-3-ol (125 mg) obtained in Example25 was dissolved in toluene (2 mL). Benzoic acid (214 mg), a 40 wt %solution (705 mg) of diethyl azodicarboxylate in toluene, andtriphenylphosphine (416 mg) were added. The mixture was stirredovernight. After the reaction, 10% of the solution was purified by flashchromatography to give the title compound (12 mg) (88% ee), which wasalmost a pure anti-form.

¹H-NMR(CDCl₃, δppm): 1.94-2.01(1H, m), 2.10-2.15(1H, m), 3.17-3.23(1H,m), 3.94(1H, dd, J=10 Hz, J=6 Hz), 3.99-4.05(2H, m), 4.20(1H, dd, J=10Hz, J=6 Hz), 5.45-5.51(1H, m), 5.80(1H, d, J=5 Hz), 7.47(2H, t, J=8 Hz),7.58(1H, t, J=8 Hz), 8.04(1H, d, J=8 Hz)

Example 27

Synthesis of (3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (compound (XV))

Toluene (20 mL) was added to 90% of the solution after reaction, whichwas obtained in Example 26, and the mixture was washed 3 times withwater (20 mL). The solvent was evaporated and methanol (20 mL) was addedto the residue. 10% Aqueous sodium hydroxide solution (20 mL) was pouredthereinto and the mixture was stirred for 30 min. The solvent wasevaporated and water (30 mL) was poured into the residue. The mixturewas washed twice with toluene (20 mL) and sodium chloride was added tothe aqueous layer to saturation. The mixture was extracted 3 times withethyl acetate (20 mL) and dried over anhydrous magnesium sulfate. Thesolvent was evaporated to give the title compound (98 mg, 88% ee) as anoil, which was an almost pure anti-form.

¹H-NMR(CDCl₃, δppm): 1.73(1H (—OH), d, J=6 Hz), 1.82-1.93(1H, m),2.28-2.34(1H, m), 2.82-2.89(1H, m), 3.65(1H, dd, J=9 Hz, J=7 Hz),3.88-3.94(1H, m), 3.97-4.02(2H, m), 4.42-4.49(1H, m), 5.70(1H, d, J=5Hz).

The optical purity was measured by HPLC under the following conditionsafter benzoylation by a conventional method. HPLC condition: DaicelChiralcel OD-H (0.46 cmφ×25 cm, 19/1 hexane/2-propanol; 1 ml/min, 254nm) (3S,3aR,6aS)-form t_(r)=13 min, (3R,3aS,6aR)-form t_(r)=14 min

Example 28

Synthesis of (3aR,6aS)-hexahydrofuro[2,3-b]furan-3-on (compound (XXVII))

A solution of oxalyl chloride (510 mg) in methylene chloride (10 mL) wascooled to −78° C. and a solution of dimethyl sulfoxide (421 mg) inmethylene chloride (2 mL) was added dropwise. The mixture was stirredfor 10 min and a solution of (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol(260 mg, 88% ee) obtained in Example 25 in methylene chloride (5 mL) wasadded dropwise at the same temperature. The mixture was stirred for 15min and the reaction mixture was warmed to −45° C. over 1 hr.Triethylamine (2.4 mL) was poured thereinto and the mixture was warmedto 0° C. Saturated aqueous ammonium chloride solution (8 mL) was addedto the reaction mixture and the mixture was extracted twice with ethylacetate (20 mL). The organic layer was washed with saturated aqueousammonium chloride solution and the solvent was evaporated. The residuewas purified by flash chromatography to give the title compound (82 mg,88% ee) as crystals.

¹H-NMR(CDCl₃, δppm): 2.20-2.26(2H, m), 2.97-3.01(1H, m), 3.77-3.83(1H,m), 4.03-4.07(1H, m), 4.15(2H, s), 6.07(1H, d, J=5 Hz).

Example 29

Synthesis of (3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (compound (XV))

To a suspension of lithium aluminum hydride (15 mg) dispersed in THF(0.2 mL) was added dropwise a solution of(3aR,6aS)-hekahydrofuro[2,3-b]furan-3-on (64 mg) obtained in Example 28in THF (0.5 mL) at 0° C. and the mixture was stirred for 1 hr. Water(0.1 mL), 15% aqueous sodium hydroxide solution (0.1 mL) and water (0.3mL) were successively added to the reaction mixture every 30 min and themixture was filtered and washed well with THF. The filtrate was driedover anhydrous magnesium sulfate, filtered and the solvent wasevaporated to give the title compound (57 mg, 88% ee) as an oil, whichwas an almost pure anti-form. The spectrum data were the same as thosein Example 27.

Example 30

Synthesis of (1′S,2S)-2-[2′-benzyloxy-1′-hydroxyethyl]-4-butanolide(compound (XXII))

In the same manner as in Example 22 except that2-benzyloxyacetyl-γ-butyrolactone (14.2 g) was used and (R)-(+)-BINAPwas used instead of (S)-(−)-BINAP, the title compound (10.8 g) wasobtained as an oil. The syn:anti diastereomer ratio of the obtainedproduct was 12:1, and the optical purity of the syn-form (1′S,2S-form)was 82% ee. The spectrum data were the same as those in Example 22.

Example 31

Synthesis of (2S,4′S)-2-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)-4-butanolide (compound (XXIV))

In the same manner as in Example 23 except that(1′S,2S)-2-[2′-benzyloxy-1′-hydroxyethyl]-4-butanolide (10.7 g) obtainedin Example 30 was used instead of(1′R,2R)-2-(2′-benzyloxy-1′-hydroxyethyl)-4-butanolide, the titlecompound (6.8 g) was obtained as an oil. The spectrum data were the sameas those in Example 23.

Example 32

Synthesis of(3S,4′S)-3-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)tetrahydrofuran-2-ol(compound (XXV))

In the same manner as in Example 24 except that(2S,4′S)-2-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)-4-butanolide (5.4 g)obtained in Example 31 was used instead of(2R,4′R)-2-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)-4-butanolide, thetitle compound (4.7 g) was obtained as an oil. The spectrum data werethe same as those in Example 24.

Example 33

Synthesis of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (compound(XXVI))

In the same manner as in Example 25 except that(3S,4′S)-3-(2′,2′-dimethyl-[1′,3′]dioxolane-4-yl)tetrahydrofuran-2-ol(3.2 g) obtained in Example 32 was used instead of(3R,4′R)-3-(2′,2′-dimethyl-[1′,3′]dioxolane-4′-yl)tetrahydrofuran-2-ol,the title compound (1.5 g) was obtained as pale yellow crystals. Thespectrum data were the same as those in Example 25.

Example 34

Synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl benzoate(compound (XXVIII))

In the same manner as in Example 26 except that(3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (1.0 g) obtained in Example33 was used instead of (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol andby separating and purifying a part, the title compound was obtained asan oil. The spectrum data were the same as those in Example 26. Theoptical purity was 89% ee.

Example 35

Synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (compound (XV))

In the same manner as in Examples 26, 27 except that(3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (1.0 g) obtained in Example33 was used instead of (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol, thetitle compound (0.72 g, 89% ee) was obtained as an oil. The spectrumdata were the same as those in Example 27.

INDUSTRIAL APPLICABILITY

According to the present invention, a production method of a compoundrepresented by the formula (XIV), particularly the formula (XV), usefulas an intermediate for an anti-AIDS drug, free of using ozone oxidationor highly toxic reagent, as well as an intermediate to be used for themethod and a production method thereof can be provided. In addition, amethod for efficiently producing a compound having an absoluteconfiguration represented by the formula (XV) and an enantiomer thereofwithout using a technique such as optical resolution and the like or ahighly toxic reagent, as well as an intermediate to be used for themethod and a production method thereof can be provided. Furthermore,according to the present invention, a compound represented by theformula (XIV), particularly the formula (XV), can be providedeconomically on an industrial scale.

This application is based on a patent application Nos. 382584/2002 and171303/2003 filed in Japan, the contents of which are herebyincorporated by reference.

1. A compound of the formula (C):

wherein R, R₁ and R₃ are the same or different and each independently isa hydroxy-protecting group or a hydrogen atom and R₆ is a hydroxylgroup, a lower alkoxyl group or a lower alkylthio group, or a saltthereof.
 2. The compound of claim 1, which has an absolute configurationrepresented by the formula (F):

wherein R, R₁, R₃ and R₆ are as defined in claim 1, or an enantiomerthereof.
 3. The compound of claim 1 or 2, wherein R is a benzyl group,R₁ is a hydrogen atom, R₃ is a benzyl group or a t-butyl group, and R₆is a hydroxyl group or an ethoxy group.
 4. A production method of acompound represented by the formula (XIX):

wherein P_(G) and R₂ are as defined above, and R₃ is ahydroxy-protecting group or a hydrogen atom, which uses a compoundrepresented by the formula (XIII):

wherein P_(G) is a hydroxy-protecting group, and R₂ is a lower alkoxylgroup or a lower alkylthio group, as a material.
 5. A production methodof a compound represented by the formula (XX):

wherein P_(G) and R₃ are as defined below, which comprises hydrolysis ofa compound represented by the formula (XIX):

wherein P_(G) is a hydroxy-protecting group, R₂ is a lower alkoxyl groupor a lower alkylthio group, and R₃ is a hydroxy-protecting group or ahydrogen atom.
 6. The production method of claim 5, which comprisesaddition of an organic amine after hydrolysis.